Diaryl ethers and processes for their preparation and herbicidal and desiccant compositions containing them

ABSTRACT

Diaryl ether compounds useful in the control of weeds are described. An exemplary compound is represented by the general formula (I):                    
     In this formula Q is represented by Q 9 :                    
     X and Y represent a hydrogen atom, halogen atom, cyano group, nitro group or (C 1-6 )haloalkyl group. A 1  and A 2  are independently oxygen or sulfur atoms. R 9  and R 10  represent a hydrogen atom, a (C 1-6 )alkyl group, an acyl group, or a (C 1-6 )alkylsulfonyl group; or R 9  and R 10  may form a ring consisting of polymethylene, (CH 2 ) m  groups, where m is an integer of 2, 3, 4 or 5, together with the nitrogen atom of NR 9 R 10 , which may or may not have a (C 1-6 )alkyl substituent. Methods of making the compounds are also described.

This application is the U.S. national stage application under 37 C.F.R. §371 of International Application No. PCT/US98/00209 filed Jan. 14, 1998 and is a continuation-in-part application of U.S. Ser. No. 08/947,900 filed Oct. 9, 1997, now abandoned, which is a continuation-in-part of U.S. Ser. No. 08/818,061 filed Mar. 14, 1997 now abandoned; and also is a continuation-in-part of U.S. Ser. No. 08/917,682, filed Aug. 26, 1997, now abandoned.

TECHNICAL FIELD

A class of diaryl ethers and compositions thereof which are useful in the control of weeds is of the general formula

wherein

X, Y are hydrogen, halogen, cyano, nitro, or (C₁₋₆)haloalkyl;

Z is oxygen or sulfur;

Q is selected from

Ar is a substituted or unsubstituted aryl or heteroaryl ring; When Q is Q₃ or Q₆, substituted phenyl is excluded.

BACKGROUND ART

Various substituted phenyl ethers (I¹) are known in the literature.

Q may be pyrazole, imidazole, imidazolidine-2,4-dione, triazolinone, tetrazolinone, aminouracil, etc. R may be hydrogen, alkyl, cycloalkyl, alkenyl or alkynyl. U.S. Pat. No. 5,496,956 discloses arylpyrazoles with the R group selected from propargyl, allyl, or substituted alkyl. JP 6,256,312 discloses phenylimidazoles with the R group selected from hydrogen, (C₁₋₁₀)alkyl, (C₁₋₅)haloalkyl, (C₃₋₅)alkenyl, (C₃₋₅)alkynyl, or (C₃₋₆)cycloalkyl. U.S. Pat. No. 5,125,958 discloses triazolinones with the R group selected from substituted phenyl group. JP 57,197,268 discloses hydantoins with the R group selected lower alkyl. U.S. Pat. No. 4,902,337 discloses hydantoins with the R group selected from hydrogen, alkyl, cycloalkyl, alkenyl or alkynyl. JP 525173 discloses pyrimidinediones with the R group selected from hydrogen, (C₁₋₁₀)alkyl, (C₁₋₅)haloalkyl, (C₃₋₅)alkenyl, (C₃₋₅)alkynyl, or (C₃₋₆)cycloalkyl. U.S. Pat. No. 4,985,065 discloses phenyltetrazolinones with the R group selected from substituted phenyl group. No heteroaryl derivatives were claimed as R. WO 9,602,523 discloses substituted aryliminothiadiazoles with the R group selected from hydrogen, alkyl, cycloalkyl, alkenyl or alkynyl. U.S. Pat. No. 4,452,981 discloses phenylurazoles with the R group selected from (C₁₋₃)alkyl, allyl, or propargyl. EP-A-517181(which corresponds to U.S. Pat. No. 5,280,010) discloses aminouracil compounds wherein Q is amino uracil and R is a lower alkyl group. WO96/07323 and WO96/08151 disclose some known uracil compounds. In WO96/08151 the generic representation is significantly broader than the disclosures set forth in it, and in the prior art patents. The specific aminouracil compounds of the formula (I) mentioned below are not known and are novel.

The present invention reveals that some diaryl ethers represented by the general formula (I) or their salts have a potent herbicidal activity with good crop safety.

DISCLOSURE OF THE INVENTION

The need continues for novel and improved herbicidal compounds and compositions. This invention relates to novel diaryl ethers, compositions comprising diaryl ethers, and the use of diaryl ethers and compositions thereof as broad spectrum herbicides which are effective against both monocot and dicot weed species in preemergence and postemergence application and are sometimes safe to crops. The compounds and compositions of the present invention can also be sometimes used as desiccants. This invention also includes methods of preparing these compounds and intermediates thereof as well as methods of using the compound as herbicides.

This invention relates to diaryl ether compounds having the general formula I and their salts

wherein

X, Y are independently hydrogen, halogen, cyano, nitro, or (C₁₋₆)haloalkyl and

Z is oxygen or sulfur and

Q is selected from

R₁ is halogen;

R₂, R₃, R₄ and R₅ are independently hydrogen, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl;

When R₃ and R₅ are taken together with the atoms to which they are attached, they represent a four to seven membered substituted or unsubstituted ring optionally interrupted by O, S(O)_(n) or N—R₄, and optionally substituted with one to three (C₁₋₆)alkyl group or one or more halogen atoms;

R₆ is hydrogen, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl, (C₂₋₆)haloalkenyl, (C₂₋₆)haloalkynyl, (C₁₋₆)cyanoalkyl, (C₁₋₆)alkoxy-(C₁₋₆)alkyl, or (C₁₋₆)alkylthio-(C₁₋₆)alkyl;

A₁ and A₂ are independently oxygen or sulfur;

B is CH or N;

R₇ and R₈ are each independently hydrogen, (C₁-₆)alkyl optionally substituted with one or more halogen atoms, or (C₃₋₆)cycloalkyl optionally substituted with one or more halogen atoms, and when R₇ and R₈ are taken together with the atoms to which they are attached, they represent a four to seven membered substituted or unsubstituted ring optionally interrupted by O, S(O)_(n) or N—R₄, and optionally substituted with one to three (C₁₋₆)alkyl groups or one or more halogen atoms;

n is an integer of 0, 1, or 2.

R₉ and R₁₀ are hydrogen, (C₁₋₆)alkyl, acyl, or (C₁₋₆)alkylsulfonyl or R₉ and R₁₀ may form a ring consisting of polymethylene, (CH₂)_(m) groups, where m is an integer of 2, 3, 4 or 5, together with the nitrogen atom of NR₉R₁₀, which may or may not have a (C₁₋₆)alkyl substituent.

Some compounds of formula (1) and their intermediates may occasionally exist as geometrical or optical isomers and the present invention includes all of these isomeric forms

Some compounds of the formula (I) and their intermediates may form a salt with an acidic substance or a basic substance. The salt with an acidic substance may be an inorganic acid salt such as a hydrochloride, a hydrobromide, a phosphate, a sulfate or a nitrate. The salt with a basic substance may be a salt of an inorganic or organic base such as a sodium salt, a potassium salt, a calcium salt, a quartemary ammonium salt such as ammonium salt or a dimethylamine salt.

Ar is a substituted or unsubstituted aryl or heteroaryl ring; When Q is Q₃ or Q₆, substituted phenyl is excluded.

This invention also relates to compositions containing those compounds and methods for using those compounds and compositions. The compounds and compositions of the present invention are especially useful for the selective control of undesirable plant species occasionally in the presence of crops. The compounds and compositions of the present invention can also be used as desiccants.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for controlling undesirable plant species by preemergence or postemergence application.

The diaryl ether compounds of this invention have the general formula I

wherein X, Y, Z, Ar, and Q are as described above.

The aryl in the definition of Ar may be phenyl or naphthyl, and the heteroaryl in the definition of Ar may be a five or six membered ring having at least one heterogeneous atom of nitrogen, oxygen or sulfur, and for example may be pyridyl, pyrimidyl , pyridazinyl, triazolyl, thiazolyl or isothiazolyl. The substituents for the substituted aryl or heteroaryl ring may, for example, be halogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, halo(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, (C₁₋₆)alkylsulfonyl, (C₁₋₆)alkylsulfinyl, (C₁₋₆)dialkylaminocarbonyl, cyano, nitro, amino, hydroxy, (C₁₋₆)alkylsulfonylamino, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkoxy, (C₁₋₆)alkylcarbonylamino, bisbenzoylamino, aminoacetyl, aminotifluoroacetyl, or amino(C₁₋₆)allylsulfonate. The number of substituents is one or more, for example up to five. When the number is two or more, the substituents may be same or different.

The alkyl group and alkyl part in the definition related to X, Y, R₂ to R₁₀ and the substituents for the substituted aryl and heteroaryl ring as Ar have the straighted or branched chains with C₁₋₆, preferably C₁₋₄ such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. The alkenyl or alkynyl group and their parts in the definition for R₆ have also the straighted or branched chains with C₂₋₆, preferably C₂₋₄ such as vinyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

The halogen atom and halogeno part in the definition related to X, Y, R₁ to R₈ are fluorine, chlorine, bromine, or iodine. The haloalkyl, haloalkenyl or haloalkynyl group constitutes the alkyl, alkenyl or alkynyl group and one or more halogen atoms as mentioned above. When the number of halogen atom is two or more, halogen atoms may be same or different.

Preferred formula I compounds of this invention are those wherein

X, Y are independently hydrogen, or halogen;

Z is oxygen or sulfur;

Q is selected from Q₁, Q₂, Q₄, Q₆, Q₇, Q₈, or Q₉.

Ar is pyridyl, pyrimidyl, triazolyl, thiazolyl, isothiazolyl, or phenyl or pyridyl, pyrimidyl, triazolyl, thiazolyl, isothiazolyl, or phenyl substituted with up to five substituents independently selected from bromo, chloro, fluoro, iodo, (C₁-C₄)alkyl, halo(C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₄)alkylthio, halo(C₁₋₄)alkoxy, (C₁₋₄)alkylsulfonyl, (C₁-C₃)alkylsulfinyl, di(C₁₋₄)alkylaminocarbonyl, cyano, nitro, amino, hydroxy, (C₁₋₄) alkylsulfonylamino, (C₁₋₄)alkoxycarbonyl(C₁₋₄)alkoxy, or (C₁₋₄)alkoxycarbonylamino; When Q is Q₆, substituted phenyl is excluded.

The most preferred formula I compounds of this invention are those wherein

X is fluorine;

Y is chlorine;

Z is oxygen or sulfur;

Q is selected from Q₁, Q₂, Q₄, Q₆, Q₇, Q₈, or Q₉.

Ar is 2-pyridyl, 3-pyridyl , 4-pyridyl , 3-bromo-2-pyridyl, 5-bromo-2-pyridyl, 6-bromo-2-pyridyl, 3-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3-cyano-2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 3-nitro-2-pyridyl, 5-nitro-2-pyridyl, 6-nitro-2-pyridyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 5-amino-2-pyridyl, 3-dimethylaminocarbonyl-2-pyridyl, 3-methylsulfonyl-2-pyridyl, 3-isopropylsulfonyl-2-pyridyl, 6-chloro-3-trifluorometbyl-2-pyridyl, 3,5,6-trifluoropyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-bromo-2-pyrimidyl, 4-chloro-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl, 4,6-dimethoxy-2-pyrimidyl, 2,6-dimethoxy-4-pyrimidyl, 4,6-dimethoxy-2-triazinyl, phenyl, 2-iodophenyl, 2-trifluoromethoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-methylsulfonylaminophenyl, 4-(1-ethoxycarbonylethoxy)phenyl, 2-cyanophenyl, 2-cyano-3-fluorophenyl, 2-cyano-4-fluorophenyl, 2-amino-4-(1-ethoxycarbonylethoxy)-phenyl, 2-cyano-4-nitrophenyl, 4-amino-2-cyanophenyl, 4-nitro-2-trifluoromethylphenyl, 4-amino-2-trifluoromethylphenyl, 4-acetylamino-2-trifluoromethylphenyl, 4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 5-chloro-4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 3-methyl-4-nitro-5-isothiazolyl,or 5-nitro-2-thiazolyl; When Q is Q₆, substituted phenyl is excluded.

The intermediates II and III can be prepared by the methods mentioned in Process (1).

Process (1) is carried out in two stages. The first step is the reaction of an aminophenol with an aryl halide or an heteroaryl halide with or without solvents. The solvents may include acetonitrile, tetrahydrofuran, dimethyl imidazolidine, dimethylsulfoxide, hexamethylphosphoric triamide, N,N-dimethylformamide, acetone, butan-2-one, benzene, toluene or xylene, in the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium t-butoxide, potassium fluoride, or sodium hydride. Catalysts may or may not be used. Such catalysts include copper(1)chloride, copper(1)oxide, copper, copper(1)alkoxide, alkyl cuprate, palladium(0), tetrabutylammonium halides, or 8-quinolinol. The reaction temperature is usually from 0° C. to 250° C., preferably from 20° C. to 120° C. The reaction time is from 1 to 12 hours, preferably from 2 to 6 hours. The diaryl ethers (II) may also be prepared by treatment of an aminophenol with aryl-lead tricarboxylates, triphenylbismuth-diacetate, triphenylbismuth-trifluoroacetate or diphenyliodonium halides in the presence of solvents such as benzene, toluene, dichloromethane, dichloroethane, chloroform or water, with or without catalysts such as copper, or a transition metal. The temperature is usually from 0° C. to the reflux temperature of the mixture, and the reaction time from 10 minutes to 72 hours. The temperature is preferably from 20° C. to the reflux temperature of the mixture, and the time preferably 2 to 6 hours.

The second step requires treatment of the amine (II) with phosgene or triphosgene in a solvent such as hexane, heptane, benzene, toluene, xylene, or ethyl acetate. The reaction temperature is usually from 0° C. to the reflux temperature of the mixture, preferably at the reflux temperature of the mixture. The reaction time is usually from 30 minutes to 6 hours, preferably from 2 to 3 hours.

In Process (2) the ether linkage is formed using the conditions described in the first stage of Process (1).

In Process (3) the ether linkage is formed using the conditions described in the first stage of Process (1).

Process (4) proceeds in three stages. The first step is the formation of a diazonium salt of aniline (II) usually in an acidic medium such as conc. hydrochloric acid when treated with aqueous sodium nitrite solution. It is reduced in the presence of a reducing agent to give the corresponding hydrazine derivative. Such a reducing agent could be an inorganic compound such as hydrated tin(II)chloride. This is treated with a ketoacid such as pyruvic acid in aqueous solution. The reaction temperature is between −15° C. to 30° C. and the time from 30 minutes to 4 hours. The preferred temperature initially is between 0° C. and 5° C. and later at 20° C. to 30° C. and the preferred time is from 30 to 60 minutes.

In the second step the prepared hydrazone (VIII) is treated with diphenylphos-phoryl azide in an inert solvent such as benzene, toluene, xylene, hexane, in the presence of a base such as triethylamine or pyridine. The reaction temperature is between 20° C. and the reflux temperature of the mixture and the time from 30 minutes to 6 hours. Preferably the temperature is the reflux temperature of the mixture and the time is from 1 to 2 hours.

The final stage is the alkylation of (IX) in an inert solvent such as diethyl ether, dioxane or tetrahydrofuran with an alkylating agent such as an alkyl halide, haloalkyl halide, or alkyl sulfate, in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, pyridine or triethylamine with or without a catalytic amount of a tetraalkylammonium salt. The reaction temperature is between −40° C. to 50° C. and the time from 30 minutes to 4 days. The preferred reaction temperature is between 20° C. to 30° C., the preferred reaction time is 2 days.

Process (5) proceeds in three stages. The first step is the treatment of the isocyanate (IIIa) with ammonia in an inert solvent such as hexanc, benzene, toluene, xylene, diethyl ether, tetrahydrofuran or dioxane. The reaction temperature is between −10° C. to 100° C. and the time from 15 minutes to 6 hours. The reaction temperature is preferably between 0° C. and 10° C., and the time from 30 to 60 minutes.

The second step is the treatment of the urca (XI) with an acid catalyst such as p-toluenesulfonic acid or amberlyst resin. and a ketoester, in an inert solvent such as benzene, toluene, xylene, hexane, at a temperature between 20° C. and the reflux temperature of the mixture, from 10 to 24 hours, to give the imidazolidinone (XII). The temperature is preferably the reflux temperature of the mixture and the time 12 to 16 hours.

The final stage is the alkylation of (XII) in an inert solvent such as diethyl ether, dioxane, tetrahydrofuran, benzene, toluene, xylene or hexane, with an alkylating agent such as an alkyl halide or haloalkyl halide, in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, pyridine or triethylamine. The reaction temperature is between 20° C. to the reflux temperature of the mixture, and the time from 30 minutes to 20 hours. Preferably the temperature is between 50° C. and 100° C. and the time from 12 to 16 hour.

Process (6) proceeds in three stages. The first step is the treatment of the isocyanate (IIIb) with 2,2-dimethyl-5-(2-tetrahydropyrrolylidene)-1,3-dioxane-4,6-dione in the presence of a base such as sodium methoxide, sodium ethoxide, potassium t-butoxide, or sodium hydride in a solvent such as toluene, N,N-dimethylformamide or dimethylsulfoxide. The reaction temperature is between −40° C. to the reflux temperature of the mixture and the time from 30 minutes to 14 hours. Preferably the initial temperature of the addition is between −30° C. to −20° C., and further reaction requires temperatures of between 100° C. and 120° C. The preferred time is from 4 to 5 hours.

The second step is the hydrolysis of the ether linkage under acidic conditions in an inert solvent such as chloroform or ethylene chloride, using conc. sulfuric acid. The reaction temperature is between −20° C. to 50° C. and the time from 30 minutes to 6 hours. Preferably the addition is done at between 0° C. to 5° C., and further reaction requires temperatures of between 20° C. and 30° C. The preferred time is from 1 to 2 hours.

In the final step the ether linkage is formed using the conditions described in the first stage of Process (1).

Process (7) proceeds in two stages. The first step is the formation of the tetrazole ring (XVIII) by treatment of the isocyanate (III) with trimethylsilyl azide with or without solvent. The reaction temperature is between 100° C. to the reflux temperature of the mixture and the time from 1 to 48 hours. Preferably the temperature is the reflux temperature of the mixture and the time 24 hours.

The final stage is the alkylation of (XVIII) in an inert solvent such as acetone, diethyl ether, dioxane, tetrahydrofuran, benzene, toluene, xylene, hexane, N,N-dimethyl-formamide or dimethylsulfoxide, with an alkylating agent such as an alkyl halide or an haloalkyl halide in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, pyridine or triethylamine. The reaction temperature is between 50° C. to 150° C. and the time from 30 minutes to 2 days. The preferred temperature range is between 70° C. and 90° C. and the time from 20 to 30 hours.

Process (8) proceeds in five stages. The first step requires treatment of the amine (II) with thiophosgene in a solvent such as hexane, heptane, benzene, toluene, xylene, or ethyl acetate. The reaction temperature is usually from 0° C. to the reflux temperature of the mixture, preferably the addition is done at 0° C. to 5° C., and further reaction requires temperatures heating to the reflux temperature of the mixture. The reaction time is usually from 30 minutes to 6 hours, preferably from 2 to 3 hours.

In the second step the isothiocyanate (XX) was treated with formic hydrazide in an inert solvent such as toluene, tetrahydrofuran, dioxane or diethyl ether. The reaction temperature is usually from 0° C. to the reflux temperature of the mixture, preferably at ambient temperature. The reaction time is usually from 30 minutes to 10 hours, preferably from 3 to 4 hours.

The formyl hydrazines (XXI) were treated with phosgene or triphosgene in a solvent such as hexane, heptane, benzene, toluene, xylene, acetone, or ethyl acetate. The reaction temperature is usually from −20° C. to 50° C., preferably between 0° C. and 25° C. The reaction time is usually from 30 minutes to 6 hours, preferably from 1 to 2 hours.

The hydrolysis of the 3-formylthiadiazolidinones (XXII) is done under acidic conditions in such solvents as acetone, butan-2-one, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide. The acids may be sulfuric, hydrochloric or acetic acids and may be diluted. The reaction temperature is usually from −20° C. to 50° C., preferably between 0° C. and 25° C. The reaction time is usually from 15 minutes to 6 hours, preferably from 30 minutes to 2 hours.

The final stage is the alkylation of (XXIII) in an inert solvent such as acetone, diethyl ether, dioxane, tetrahydrofuran, benzene, toluene, xylene, hexane, N,N-dimethyl-formamide or dimethylsulfoxide, with an alkylating agent such as an alkyl halide or a haloalkyl halide, in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, pyridine or triethylamine. The reaction temperature is between 30° C. to the reflux temperature of the mixture and the time from 30 minutes to 6 hours. The preferred temperature range is between 50° C. and 90° C. and the time from 1 to 3 hours.

In Process (9) amines (II) are transformed into the 2,4-imidazolidinediones (XXVII) in three stages. In the first step treatment with a haloacetyl halide, such as chloroacetyl chloride and an organic base such as triethylamine or pyridine, in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, or N,N-dimethylformamide gave the chloroamides (XXV). The preferred acylating agent is chloroacetyl chloride and the preferred base triethylamine. The preferred solvent is toluene. The reaction may be carried out at temperatures between −20° C. and 150° C., preferably between 25° C. and 50° C. The reaction time may be from 30 minutes to 10 ten hours, preferably between 2 and 4 hours.

In the second step reaction of these chloroamides (XXV) with suitable amines in a solvent such as C₁₋₅ alcohols, tetrahydrofuran, or dioxane gave amino-amides (XXVI). The preferred solvent is ethanol, and the reaction may be carried out at temperatures between −20° C. and 150° C., preferably between 25° C. and 70° C. The reaction time may be from 30 minutes to ten hours, preferably between 2 and 3 hours.

In the third step the amino-amides (XXVI) are treated with 1,1¹-carbonyldi-imidazole in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, or N,N-dimethylformamide and yielded the 2,4-imidazlidinediones(XXVII). The preferred solvent is toluene, and the reaction may be carried out at temperatures between −20° C. and 150° C., preferably between 100° C. and 120° C. The reaction time may be from 30 minutes to ten hour, preferably between 2 and 3 hours.

Process (10) proceeds in three stages. The first is the reaction of isothiocyanates (XXa) with a saturated cyclic heterocycle (XXVIII) such as 1-ethyloxycarbonylhexahydropyridazine, where B=N and f=2, and may or may not be done in two parts, (1) and (2). In part (1) they are stirred together in an inert solvent such as benzene, toluene, xylene, dioxane, hexane, ethyl acetate, tetrahydrofuran, diethyl ether, or acetone. The reaction temperature is usually from −70° C. to the reflux temperature of the mixture, depending on the nature of B, f, and R₄. The reaction time is usually from 30 minutes to 20 hours, depending on the nature of B, f, and R₄. In part (2) after removal of the solvent toluene, xylene, or dioxane may be added, and also a weakly basic compound such as sodium acetate. The reaction proceeds at a temperature of between 50° C. to the reflux temperature of the mixture and the time from 6 hours to 3 days. The preferred temperature is the reflux temperature of the mixture and the time from 20 to 30 hours.

The second step is the hydrolysis of the ether linkage under acidic conditions in an inert solvent such as chloroform or methylene chloride, using conc. sulfuric acid. The reaction temperature is between −20° C. to 50° C. and the time from 30 minutes to 6 hours. Preferably at 0° C. and a time of 1 to 2 hours.

The final step is the formation of the ether linkage to give (XXXI). This is done using the conditions described in the first stage of Process (1).

Process (11) is a one step process where a compound (XXb), which may be an isocyanate or an isothiocyanate, reacts with a saturated cyclic heterocycle (XXVIII), with or without solvents, to give the product (XXXI). The reaction is enhanced by the presence of solvents such as hexane, pentane, benzene, toluene, xylene, diethyl ether, tetrahydro-furan, dioxane, acetone, butan-2-one, ethyl acetate, N,N-dimethylformamide or dimethyl-sulfoxide, and is conducted between −70° C. to the reflux temperature of the mixture and from 15 minutes to 20 hours. The temperature is preferably between 0° C. and 30° C., and the time from 15 minutes to 12 hours.

In Process (12) the thiadiazabicyclononanones (XXIV) are treated with a catalytic amount of a base such as sodium methoxide, sodium ethoxide, or potassium t-butoxide in a C₁₋₅ alcohol such as methanol, ethanol or t-butanol, at a temperature between 0° C. and the reflux temperature of the mixture from 15 minutes to 3 hours. Preferably at the reflux temperature of the mixture and from 30 to 60 minutes.

Process (13) is carried out using 0.5 to 10 equivalents (preferably 0.8 to 3) of the hydrazines relative to the oxazines (XXXII). Examples of hydrazines include hydrazine, alkyl hydrazines such as methyl, ethyl, or t-butylhydrazine, and cyclic hydrazines such as 1-aminopyrrolidine. The reaction proceeds without any solvents but is normally accelerated by employing solvent.

Further reaction requires solvents such as aliphatic hydrocarbons e,g, hexane, heptane, ligroin and petroleum ether, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as diethyl ether, dioxane, and tetrahydrofuran, ketones such as acetone and methyl ethyl ketones, nitrites such as acetonitrile and isobutyronitrile, tertiary amines such as pyridine and N,N-dimethylaniline, acid amides such as N,N-dimethyl-acetamide, N,N-dimethylformamide, and N-methylpyrrolidone, sulfur containing compounds such as dimethylsulfoxide and sulfolane, alcohols such as methanol, ethanol, propanol, and butanol, water and the mixtures thereof.

The reaction temperature is usually from −30° C. to 150° C., preferably from −10° C. to the reflux temperature of the reaction mixture. The reaction time requires normally from 10 minutes to 96 hours, preferably from 30 minutes to 48 hours.

In Process (14) the ether linkage is formed using the conditions described in the first stage of Process (1).

Process (15) is carried out in a solvent such as dioxane, dimethylsulfoxide, hexamethylphosphoric triamide or N,N-dimethylformamide in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydride. A number of aminating agents may be used such as 2,4-dinitro-phenoxyamine; O-arylsulfonylhydroxyamines such as 2,3,6-trimethyl- and triisopropyl-phenylhydroxyamine; O-picoylhydroxyamine; and O-mesitylhydroxyamine. The reaction temperature is usually from −30° C. to 110° C., and the reaction time is from 12 hours to 7 days. The reaction temperature is preferably from 20° C. to 30° C. The reaction time is preferably from 12 hours to 3 days.

Using Process (16) the isocyanate (III) may be used to form the aminouracil (XXXIIIa) in a one pot synthesis without isolating the uracil (XXXV). The uracil ring is formed by reacting the prepared isocyanate (III) with an alkyl 3-amino-4,4,4-trifluoro-crotonate and a base such as sodium hydride, sodium methoxide or sodium ethoxide, in a solvent such as dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene, xylene, tetrahydrofuran, dioxane, or diethyl ether, at temperatures usually from −50° C. to 50° C., with a reaction time from 10 minutes to 14 hours. Preferably between −30° C. to 30° C., with a reaction time of 15 minutes to 6 hours. Aminating agents, such as 2,4-dinitro-phenoxyamine; O-arylsulfonylhydroxyamines such as 2,3,6-trimethyl- and triisopropyl-phenylhydroxyamine; O-picoylhydroxyamine; and O-mesitylhydroxyamine are then introduced, as described for Process (15). The reaction temperature is usually from −30° C. to 110° C., and the reaction time is from 12 hours to 7 days. The reaction temperature is preferably from 20° C. to 30° C. The reaction time is preferably from 12 hours to 3 days.

Using Process (17) a compound of formula (Q₉) wherein A₁ and/or A₂ are/is a sulfur atom, can be prepared by reacting a compound of the above formula (XXXIII) with a sulfurizing agent such as Lawesson's reagent or phosphorus pentasulfide. Further sulfurization may occur with prolonged heating and with excess reagent. The reaction uses solvents such as benzene, toluene and xylene. The reaction time is usually 2 to 12 hours, preferably 3 to 4 hours The reaction temperature is usually 0° C. to 150° C., preferably between 60° C. and the reflux temperature of the mixture.

In Process (18) the ether linkage is formed using the conditions described in the first stage of Process (1).

Process (19) requires the reaction of the sodium or potassium salt of an aromatic- or heterocyclic hydroxyl compound with the haloaromatic uracil (XXXVIII). The reaction proceeds without any solvent but is normally accelerated by employing solvent. These include toluene, xylene, N,N-dimethylformamide, and dimethylsulfoxide, and a catalyst is used such as copper, copper bronze, or a transition metal. The temperature is usually from 0° C. to 150° C., and the reaction time from 10 minutes to 72 hours. The temperature is preferably from 150° C. to the reflux temperature of the mixture, and the time preferably 2 to 6 hours.

Process (20) shows how the uracil ring may be formed by reacting the prepared isocyanate (III) with an alkyl 3-amino-4,4,4-trifluorocrotonate and a base such as sodium hydride, sodium methoxide, sodium ethoxide, or potassium t-butoxide, in a solvent such as dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene, xylene, tetrahydro-furan, dioxane, or diethyl ether, at temperatures usually from −50° C. to 50° C., with a reaction time from 10 minutes to 14 hours. Preferably from −30° C. to 30° C., with a reaction time of 15 minutes to 6 hours.

Process (21) is carried out in two stages. The first step is the preparation of N-phenyl-acetamide (XXXIX) using conventional methodology.

The second step is the cyclization to give the oxazines (XXXII). This is carried out in solvents which are aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether, aromatic hydrocarbons such as benzene, toluene, xylene, and chloro-benzene, tertiary amines such as pyridine, and N,N-diethylaniline, acid amides such as N,N-dimethylacetamicle, N,N-dimethylformamide, and N-methylpyrrolidone, sulfur containing compounds such as dimethylsulfoxide and sulfolane, and organic acids such as formic acid, acetic acid, lactic acid, and acetic anhydride. Preferably used are the above mentioned aliphatic hydrocarbons, aromatic hydrocarbons and organic acids. The reaction temperature is usually from 0° C. to 200° C., preferably from 20° C. to the reflux temperature of the mixture. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Process (22) is carried out in two stages. The first step is the formation of the phenolic oxazine (XL) using the methodology described in Process (21). This is carried out in solvents which are aliphatic hydrocarbons such as hexanc, heptane, ligroin, and petroleum ether, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, tertiary amines such as pyridine, and N,N-diethylaniline, acid amides such as N,N-dimethylacetamide, N,N-dimetbylformamide, and N-methylpyrrolidone, sulfur containing compounds such as dimethylsulfoxide and sulfolane, and organic acids such as formic acid, acetic acid, lactic acid, and acetic anhydride. Preferably used are the above mentioned aliphatic hydrocarbons, aromatic hydrocarbons and organic acids. The reaction temperature is usually from 0° C. to 200° C., preferably from 20° C. to the reflux temperature of the mixture. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The second step is carried out under the same conditions described for Process (13).

Process (23) is carried out in two stages. The starting material for the first step, carbamates (XLI), are prepared by conventional methodology. These are treated with an alkyl 3-amino-4,4,4-trifluorocrotonate under the conditions described for Process (20). The second step is carried out under the same conditions described for Process (15).

In Process (24) the isocyanate (III) is treated with the hydrazono compound (XLIII) under the conditions described for Process (20) to give the desired product (XXXIII).

Although some embodiments of the present invention are described as follows, the scope of the present invention is not limited to such an embodiment.

Preparation Examples for the compounds of the present invention will be described. The preparation of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetra-hydropyrimidine-2,4-dione is described in U.S. Pat. No. 4,859,229. Lawesson's reagent, [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide], was obtained from Aldrich.

EXAMPLES General

All temperatures are measured in ° C., conc. means concentrated, and mp represents the melting point. Processed indicates that water and ethyl acetate were added, the solutions separated and the organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The preparation of 5-amino-2-chloro-4-fluorophenol is described in U.S. Pat. No. 4,484,941. Purity was assessed by thin layer chromatography, liquid chromatography, and checked using ¹H and ¹³C nuclear magnetic resonance spectrometry (NMR) which were obtained on a Varian 300 MHz instrument.

Example 1 Synthesis of 4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl Isocyanate (Intermediate IIIc) (Process 1).

1.1

2-(5-Amino-2-chloro-4-fluorophenoxy)pyrimidine (Intermediate IIp).

A mixture of 5-amino-2-chloro-4-fluorophenol (3.57 g), potassium carbonate (3.04 g), and 2-chloropyrimidine (3.20 g) suspended in butan-2-one (100 ml) and dimethylsulfoxide (10 ml) was heated at reflux overnight. The solution was processed and chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2, to yield yellow crystals (4.0 g). ¹H NMR (acetoned-d₆, TMS): 4.75(2H, br s), 6.78(1H, d, J=8.4 Hz), 7.09(1H, d, J=10.6 Hz), 7.15(1H, t, J=4.8 Hz), 8.56(2H, d, J=4.8 Hz).

The following can be similarly prepared:

2-(5-Amino-2-chloro-4-fluorophenoxy)-4-chloro-pyrimidine (Intermediate IIq).

2-(5-Amino-2-chloro-4-fluorophenoxy)-4,6-dimethoxy-pyrimidine (intermediate IIr).

2-(5-Amino-2,4-dichlorophenoxy)-4-chloro-pyrimidine (Intermediate IIs).

2-(5-Amino-2-chloro-4-fluorophenoxy)-nitrobenzene (Intermediate IIt).

2-(5-Amino-2-chloro-4-fluorophenoxy)-benzonitrile (Intermediate IIu).

2-(5-Amino-2-chloro-4-fluorophenoxy)-6-fluoro-benzonitrile (Intermediate IIv).

1.2

4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl isocyanate (intermediate IIIc).

A solution of triphosgene (1.21 g) in ethyl acetate (10 ml) was stirred at 0° C. under nitrogen while a solution of 2-(5-amino-2-chloro-4-fluorophenoxy)pyrimidine (0.96 g) and triethylamine (1.2 ml) in ethyl acetate (10 ml) was added dropwise. The mixture was heated at reflux for 3.5 hours, cooled, filtered, and the filtrate evaporated to give the corresponding isocyanate. ¹H NMR (CDCl₃, TMS): 7.03(1H, d, J=7.2 Hz), 7.10(1H, t, J=4.8 Hz), 7.31(1H, d, J=8.9 Hz), 8.57(2H, d, J=4.8 Hz).

The following can be similarly prepared:

4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyrimidyloxy)phenyl isocyanate (Intermediate IIId).

4-Chloro-2-fluoro-5-(2-nitrophenoxy)phenyl isocyanate (Intermediate IIIe).

4-Chloro-2-fluoro-5-(2-cyanophenoxy)phenyl isocyanate (Intermediate IIIf).

4-Chloro-2-fluoro-5-(6-fluoro-2-cyanophenoxy)phenyl isocyanate (Intermediate IIIg).

Example 2 Synthesis of 4-chloro-3-(4-chloro-2-fluoro-5-(4,6-dimethoxy-2-triazinyloxy)phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazolc (Compound 1-8) (Process 2).

4-Chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (prepared according to the procedure as described in U.S. Pat. No. 5,281,571) (0.25 g, 0.76 mMol) was dissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (0.13 g, 0.91 mMol) and 2-chloro-4,6-dimethoxytriazine (0.16 g, 0.91 mMol) were added. The suspension was stirred at 90° C. for 2 hours under a nitrogen atmosphere and processed. The residue was; subjected to column chromatography on silica gel eluting with methylene chloride:methanol, 99:1, to give the title compound (0.29 g, 81.6%). ¹H NMR (CDCl₃, TMS): 4.01 (6H, s), 4.07 (3H, m), 7.35 (1H, d, J=9.1 Hz), 7.45 (1H, d, J=6.6 Hz).

Example 3 Synthesis of 5-chloro-4-(4-chloro-2-fluoro-5-(4,6-dimethoxy-2-triazinyloxy)phenyl)-1-difluoromethyl-2-methylimidazole (Compound 2-4) (Process 3).

5-Chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-difluoromethyl-2-methylimidazole (prepared according to the procedure as described in EP 590,834) (0.31 g, 1 mMol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (0.17 g, 1.2 mMol) and 2-chloro-4,6-dimethoxytriazine (0.21 g, 1.2 mMol) were added and the suspension stirred at 110° C. for 2 hours under an atmosphere of nitrogen. The mixture was processed. and the residue chromatographed on silica gel eluting with methylene chloride:methanol, 98:2, to give the title compound (0.25 g, 55%). ¹H NMR (CDCl₃, TMS): 2.61 (3H, br s), 4.00 (6H, s), 7.17 (1H, t, J=58.1 Hz), 7.29 (1H, d, J=9.3 Hz), 7.53 (1H, d, J=6.6 Hz).

Example 4 Synthesis of 1-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-4-difluoromethyl-3-methyl-1,4-dihydro-1,2,4-triazolin-5-one (Compound 3-1) (Process 4).

4.1

Pyruvic acid, 4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl hydrazone.

A solution of sodium nitrite (2.01 g) in water (15 ml) was added dropwise over 10 minutes to a solution of 2-(5-amino-2-chloro-4-fluorophenoxy)pyrimidine (7.0 g) in conc. hydrochloric acid (40 ml) cooled to −10° C. and stirred under an atmosphere of nitrogen. Stirring was continued for 30 minutes at this temperature and a solution of tin(II)chloride dihydrate (16.3 g) in hydrochloric acid (20 ml) was added over 10 minutes. The resulting mixture was stirred for 2 hours at room temperature. Water (20 ml) was added and a solution of pyruvic acid (2.55 g) in water (10 ml) added dropwise. The resulting mixture was stirred for 30 minutes and the yellow precipitate was collected by filtration to give 11.24 g (wet weight) of the desired product.

4.2

1-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-3-methyl-1,4-dihydro-1,2,4-triazolin-5-one.

Triethylamine (0.4 g) was added to a suspension of pyruvic acid, 4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl hydrazone (1.24 g) in toluene (30 ml) at room temperature. Diphenylphosphoryl azide (1.05 g) was added and the resulting mixture was heated at reflux for 1 hour. The solution was processed and the residue chromatographed on silica gel eluting with ethyl acetate to give a yellow solid (0.75 g).

4.3

1-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-4-difluoromethyl-3-methyl-1,4-dihydro-1,2,4-triazolin-5-one (Compound 3-1).

Chlorodifluoromethane gas was bubbled over several hours through a solution of 1-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-3-methyl-1,4-dihydro-1,2,4-triazolin-5-one (0.43 g) in tetrahydrofuran (100 ml) stirred at room temperature, until the solution was saturated. Potassium hydroxide (0.4 g) and a catalytic amount of tetrabutyl-ammonium bromide were added and the cold bath removed. The mixture was stirred at room temperature for 48 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with ethyl acetate:hexane:methylene chloride, 1:2:2, to give a colorless oil (0.25 g).

Example 5 Synthesis of 3-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-5-isopropylidineimidazolidine-2,4-dione (Compound 4-1) (Process 5).

5.1

4Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylurea.

A solution 4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylisocyanate (1.3 g) in toluene (30 ml) was cooled to 5° C. and ammonia gas was bubbled through for 15 minutes. Stirring was continued for a further 30 minutes and the mixture filtered and the filtrate evaporated to give a white solid (1.3 g), ¹H NMR (CDCl₃) 2.40(3H, s), 7.20(5H, m).

5.2

3-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-5-isopropylidineimidazolidine-2,4-dione (Compound 4-1).

A solution 4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylurea (1.24 g), ethyl 3-methyl-2-oxobutyrate (0.9 g) and p-toluenesulphonic acid (0.1 g) in toluene (30 ml) was heated at reflux for 14 hours and processed to give a white solid (0.55 g), mp>220° C., ¹H NMR (CDCl₃) 1.90(3H, s), 2.30(3H, s), 7.12(1H, dd, J=5,7 Hz), 7.30(1H d, J=9 Hz), 8.00(1H, d, J=7 Hz), 8.25(1H, m), 8.62(1H, s).

Example 6 Synthesis of 2-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione (Compound 5-10) (Process 6).

6.1

2-4-Chloro-2-fluoro-5-isopropyloxyphenyl)-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione.

4-Chloro-2-fluoro-5-isopropyloxyaniline (9.4 g) and triethylamine (9.4 g) in dry ethyl acetate (110 ml) was stirred at 0° C. and a solution of triphosgene (13.8 g) in ethyl acetate (110 ml) was added dropwise. The mixture was heated at reflux for 2 hours, cooled to room temperature, filtered, and the filtrate evaporated. The crude isocyanate was dissolved in N,N-dimethylformamide (70 ml) and added dropwise to a mixture of sodium hydride (1.2 g) and 2, 2-dimethyl-5-(2-tetrahydropyrrolylidene)-1,3-dioxane-4,6-dione (9.9 g) in N,N-dimethylformamide (50 ml) stirred at −30° C. The mixture was stirred at room temperature for 0.5 hours and at 110° C. for 4 hours. The volume was reduced under reduced pressure and the residue processed. Column chromatography (silica gel, hexane:ethyl acetate, 2:3) yielded 2-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6,7-dihydro-pyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione, (9.0 g, 60%) ¹H NMR (CDCl₃, TMS): 1.36(6H, d, J=6.1 Hz), 2.19(2H, m), 2.99(2H, t, J=7.9 Hz), 3.99(2H, m), 4.46(1H, m), 5.74(1H, s), 6.85(1H, d, J=6.6 Hz), 7.29(1H, d, J=6.6 Hz).

6.2

2-(4-Chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione.

This was synthesized from 2-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione in 86% yield under similar conditions as described below for the preparation of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hexa-hydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.2). ¹H NMR (CDCl₃, TMS): 2.22(2H, m), 3.06(2H, t, J=7.5 Hz), 3.13(1H, br), 4.01(2H, t, J=6.5 Hz), 5.71(1H, s), 6.87)1H, d, J=6.9 Hz), 7.18(1H, d, J=9.3 Hz).

6.3

2-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione (Compound 5-10) (Process 1).

This was synthesized from 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydropyrrolo-[1,2-c]pyrimidine-1,3(2H,5H)-dione and 2-chloro-3-trifluoromethylpyridine in 90% yield under similar conditions described below for the preparation of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexabydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.3) (compound (8-29).

Example 7 Synthesis of 1-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazole (Compound 6-10) (Process 7).

7.1

1-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-1,4-dihydro-5-oxo-5H-tetrazole.

4-Chloro-²-fluoro-5-(2-pyrimidyloxy)phenylisocyanate (0.96 g) and trimethylsilyl azide (5 ml) were heated at reflux overnight under nitrogen. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with ethyl acetate:methylene chloride, 1:4, to give a yellow semi-solid (0.54 g). ¹H NMR (CDCl₃, TMS): 7.16(1H, dd, J=4.8 Hz), 7.49(1H, d, J=9.3 Hz), 7.64(1H, d, J=6.8 Hz), 8.59(2H, d, J=4.8 Hz).

7.2

1-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazole (Compound 6-10) (Process 1).

A suspension of potassium carbonate (0.36 g), 1-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-1,4-dihydro-5-oxo-5H-tetrazole (0.54 g) and 1-bromo-3-fluoropropane (0.37 g) in N,N-dimethylformamide (10 ml) was stirred in an oil bath at 80° C. for 26 hours. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 2:1, to give the product, mp 111-3° C. ¹H NMR (CDCl₃, TMS): 2.30(2H, m), 4.20(2H, t, J=6.9 Hz), 4.59(2H, dt, J=46.9, 6.6 Hz), 7.13(1H, dd, J=4.8 Hz), 7.48(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.8 Hz), 8.58(2H, d, J=4.8 Hz).

Example 8 Synthesis of 9-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-8-thia-1,6-diazabicyclo[4,3,0]nonane-7-one (Compound 7-1) (Process 8).

8.1

N-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylaminothiocarbonyl]-N¹-formylhydrazine.

Formic hydrazide (0.6 g) was added to a mixture of 4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl isothiocyanate (3.4 g) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure and the residue processed. The resulting oil was dissolved in ethanol (30 ml), and hexane added to induce crystallization. The crystals were filtered and dried to give the product, (3.5 g, 69%).

8.2

5-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-3-formyl-1,3,4-thiadiazolidin-2-one.

Triphosgene (0.7 g) in toluene (20 ml) was dropwise added to a solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl -2-pyridyloxy)phenylaminothiocarbonyl)-N¹-formyl-hydrazine (2.8 g) in acetone (70 ml) stirred at 0° C. Stirring was continued at room temperature for 1 hour and the solvents removed under reduced pressure. Column chromatography (methylene chloride:ethyl acetate, 3:1) yielded the product (3.3 g).

8.3

5-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-1,3,4-thiadiazol-idin-2-one.

A solution of 10% hydrochloric acid in methanol (8 ml) was added to a solution of 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-3-formyl-1,3,4-thiadiazolidin-2-one (3.3 g) in acetone (60 ml). After stirring for 0.5 hour, the solvents were removed and the residue processed. A minimal amount of ethanol was used to dissolved the residue and hexane added to induce crystallization. The crystals were filtered off and dried to give the product (1.0 g, 36%).

8.4

9-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-8-thia-1,6-diazabicyclo[4,3,0]nonane-7-one (Compound 7-1).

1,4-Dibromobutane (0.64 g) was mixed with 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-1,3,4-thiadiazolidin-2-one (1.0 g) in acetone (25 ml) and potassium carbonate (0.85 g) added. The mixture was heated at reflux for 2 hours and the solvent evaporated. The residue was processed and the resulting oil chromatographed (silica gel, hexane:ethyl acetate, 4:1) to give the product (0.65 g, 57%).

Example 9 Synthesis of 3-[4-chloro-2-fluoro-5-(trifluoromethyl-2-pyridyloxy)phenyl]-1-ethylimidazolidine-2,4-dione (Compound 8-1) (Process 9).

9.1

N-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-chloroacetamide.

A solution of 2-(5-amino-2-chloro-4-fluorophenoxy)-3-trifluoromethylpyridine (1.32 g) and triethylamine (0.8 ml) in toluene (20 ml) was stirred at 0° C. while a solution of chloroacetyl chloride (0.4 ml) in toluene (10 ml) was added. The mixture was stirred over night at room temperature and processed. Column chromatography on silica gel using methylene chloride as eluent gave a white solid (1.4 g), mp 146-9° C. ¹H NMR (CDCl₃, TMS): 4.20(2H, s), 7.12(1H, dd, J=5,8 Hz), 7.30(1H, d, J=9 Hz), 8.01(1H, m), 8.22(1H, m), 8.34(1H, d, J=7 Hz).

9.2

N-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide.

A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-chloroacetamide (1.4 g) and 70% ethylamine (5 ml) in ethanol (25 ml) was heated at reflux for 3 hours and evaporated to dryness. The residue was processed to give a yellow solid (1.0 g). ¹H NMR (CDCl₃, TMS): 1.16(3H, t, J=7 Hz), 2.72(2H, q, J=7 Hz), 3.39(2H, s), 7.10(1H, dd, J=6,8 Hz), 7.26(1H, d, J=8 Hz), 8.00(1H, m), 8.24(1H, m), 8.45(1H, d, J=8 Hz), 9.86(1H, s).

9.3

3-[4-Chloro-2-fluoro-5-(trifluoromethyl-2-pyridyloxy)phenyl-1-ethylimidazolidine-2,4-dione (Compound 8-1).

A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide (0.82 g) and 1,1¹-carbonyldiimidazole (0.43 g) in toluene (20 ml) was heated at reflux for 2 hours, cooled and processed. Column chromatography on silica gel eluting with 2.5% methanol-methylene chloride gave a buff colored solid (0.8 g), mp 162-3° C. ¹H NMR (CDCl₃, TMS): 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m).

Example 10 Synthesis of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Compound 8-29). (Process 10).

10.1

2-[4-Chloro-2-fluoro-5-(isopropyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyrdazin-1-one.

A solution of 4-chloro-2-fluoro-5-isopropyloxyaniline (12.1 g) and triethylamine (12.0 g) in ethyl acetate (120 ml) was cooled to 0° C. and stirred while a solution of thiophosgene (6.8 g) in ethyl acetate (100 ml) was added dropwise. The reaction was heated at reflux for 2 hours and the mixture filtered and the filtrate evaporated. The crude isothiocyanate was dissolved in benzene (70 ml) and treated with a solution of 1-ethyloxycarbonylhexahydropyridazine (9.5 g) in benzene (10 ml). After stirring for 3 hours the solvent was evaporated and the residue dissolved in m-xylene (250 ml) containing sodium acetate (1.6 g) and heated at reflux for 22 hours. The solvents were removed under reduced pressure and the residue chromatographed (silica gel, hexane:ethyl acetate, 60:40) to give the product (17.2 g, 81%). ¹H NMR (CDCl₃, TMS): 1.37(6H, d, J=7.8 Hz), 1.96(4H, m), 3.71(2H, m), 4.02(2H, m), 4.47(1H, m), 6.95(1H, d, J=6.4 Hz), 7.30(1H, d, J=9.0 Hz).

10.2

2-(4-Chloro-2-fluoro-5-hydroxyphenyl)hexahydro-3-thioxo-1H-[1,2,4]triazolol[1,2-a]pyridazin-1-one.

Conc. sulfuric acid (22 ml) was added dropwise to a solution of 2-[4-chloro-2-fluoro-5-(isopropyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (17.2 g) in methylene chloride (120 ml) stirred at 0° C. The mixture was stirred at room temperature for 1 hour and ice-water (200 g) added. The aqueous phase was extracted with methylene chloride and the organic phases combined, dried over sodium sulfate and chromatographed (silica gel, ethyl acetate) to give the product (14.5 g, 96%). ¹H NMR (CDCl₃, TMS): 1.84(4H, m), 3.82(4H, m), 7.06(1H, d, J=6.5 Hz), 7.58(1H, d, J=8.8 Hz), 10.6(1H, s).

10.3

2-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]-triazolol[1,2-a]pyridazin-1-one (Compound 8-29).

2-(4-Chloro-2-fluoro-5-hydroxyphenyl)hexahydro-3-thioxo-1H-[1,2,4]triazolo-[1,2-a]pyridazin-1-one (0.5 g) was mixed with 2-chloropyrimidine (1 equiv) and potassium carbonate (2 equiv) in dimethylsulfoxide (20 ml) and the resulting mixture stirred at 100° C. for 1.5 hour and at room temperature overnight. The mixture was processed and the residue column chromatographed (silica gel, methylene chloride:ethyl acetate, 3:1) to give the product (0.34 g, 55%). ¹H NMR (CDCl₃, TMS): 1.92(4H, m), 3.69(2H, m), 3.99(2H, m), 7.05(1H, m), 7.37(1H, d, J=6.5 Hz), 7.39(1H, d, J=9.0 Hz), 8.53(2H, d, J=4.8 Hz).

Example 11 Synthesis of 2-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Compound 8-18) (Process 11).

9-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-8-thia-1,6-diazabicyclo[4,3,0]nonan-7-one (see Example 8) (0.2 g) was mixed with methanol (18 ml) and a catalytic amount of sodium methoxide added. The mixture was heated at reflux for 0.5 hour and the solvent removed under reduced pressure. Column chromatography (silica gel, hexane:ethyl acetate, 3:2) yielded the product (0.2 g, 100%).

Example 12 (R,S)-2-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-47) (Process 11).

Thiophosgene (0.192 g) was added to a solution of 4-chloro-2-fluoro-5-(2-pyrimidyloxy)aniline (0.4 g) and triethylamine (0.34 g) in dry ethyl acetate (10 ml) and the solution was heated under reflux for 1.5 hours. After cooling, the solution was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in dry ethyl acetate (10 ml) and ethyl pipecolinate (0.288 g) was added. The solution was heated under reflux for 1 hour and evaporated to give a brown solid. This was purified using column chromatography eluting with dichloromethane to give white crystals (0.35 g). mp 238-239° C.

The following were similarly prepared:

(R,S)-2-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-hexahydro-imidazo[1,5-a]pyridin-1,3-dione (Compound 8-48).

(S)-2-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-49).

(S)-2-[4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-hexahydro-3-thioxo-pyrro[1,2-c]imidazol-1-(1H)-one (Compound 8-50).

(R,S)-2-(4-Chloro-2-fluoro-5-phenoxyphenyl)-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-51).

(R,S)-2-[4-Chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-52).

(R,S)-2-4-Chloro-5-(2-cyanophenoxy)-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-53).

(R,S)-2-[4-Chloro-2-fluoro-5-(2-pyrazinyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-54).

(R,S)-2-[4-Chloro-2-fluoro-5-(2-pyridyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-55).

(R,S)-2-[4-Chloro-5-(3-chloro-2-pyridyloxy)-2-fluorophenoxy]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-56).

(R,S)-2-[4-Chloro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-57).

(R,S)-2-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-58).

(R,S)-2-[4-Chloro-2-fluoro-5-(3-nitropyridyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-59).

(R,S)-2-[4-Chloro-5-(3-cyano-2-pyridyloxy)-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-60).

Example 13 (R,S)-2-[5-(3-Amino-2-pyridyloxy)-4-chloro-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-61).

(R,S)-2-[4-Chloro-2-fluoro-5-(3-nitropyridyloxy)phenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (0.21 g) dissolved in ethyl acetate (10 ml) was reduced under an atmosphere hydrogen using palladium-carbon (10%, 50 mg) as catalyst. After 5 hours stirring at room temperature the mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography eluting with dichloromethane:ethyl acetate, 9:1, to give a yellow oil (0.28 g).

The following was similarly prepared:

(R,S)-2-[5 -(2-Aminophenoxy)-4-chloro-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-62).

Example 14 (R,S)-2-[5-(3-Acetylamino-2-pyridyloxy)-4-chloro-2-fuorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-63).

Acetylchloride (0.047 g) was added to a solution of (R,S)-2-[5-(3-amino-2-pyridyloxy)-4-chloro-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (0.22 g) and triethylamine (0.066 g) dissolved in dry ethyl acetate (10 ml) stirred at 5° C. The solution was stirred for 1 hour at a room temperature, filtered, and the filtrate evaporated. The residue was purified by column chromatography eluting with dichloromethane: ethyl acetate, 8:2 to give brown crystals (0.24 g).

The following was similarly prepared:

(R,S)-2-[5 -[2-[(bis-Benzoyl)amino]phenoxy]4-chloro-2-fluorophenyl]-hexahydro-3-thioxo-imidazo[1,5-a]pyridin-1(5H)-one (Compound 8-64).

Example 15 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-1).

15.1

Synthesis of 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) (Process 1).

A mixture of 5-amino-2-chloro-4-fluorophenol (0.64 g), powdered potassium hydroxide (0.24 g), and 2-chloro-3-nitropyridine (0.76 g) in dimethylsulfoxide (15 ml) was heated at 110° C. with stirring for 2 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 3:97, to yield 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) as a yellow semi-solid (0.45 g).

The following were similarly prepared:

2-(5-Amino-2-chloro-4-fluorophenoxy)-5-bromopyridine (Intermediate IIb).

2-(5-Amino-2-chloro-4-fluorophenoxy)-5-chloropyridine (Intermediate IIc).

2-(5-Amino-2-chloro-4-fluorophenoxy)-6-fluoropyridine (Intermediate IId).

2-(5-Amino-2-chloro-4-fluorophenoxy)-6-chloropyridine (Intermediate IIe).

2-(5-Amino-2-chloro-4-fluorophenoxy)-3,5,6-trifluoropyridine (Intermediate IIf).

2-(5-Amino-2-chloro-4-fluorophenoxy)-3-trifluoromethylpyridine (Intermediate IIg.

2-(5-Amino-2-chloro-4-fluorophenoxy)-4-trifluoromethylpyridine (Intermediate IIh).

2-(5-Amino-2-chloro-4-fluorophenoxy)-3-cyanopyridine (Intermediate IIi).

2-(5-Amino-2-chloro-4-fluorophenoxy)-5-cyanopyridine (Intermediate IIj).

2-(5-Amino-2-chloro-4-fluorophenoxy)-5-nitropyridine (Intermediate IIk).

2-(5-Amino-2,4-difluorophenoxy)-3-trifluoromethylpyridine (Intermediate IIl).

2-(5-Amino-2-chloro-4-fluorophenoxy)-3-ethylsulfonylpyridine (Intermediate IIm).

5-(5-Amino-2-chloro-4-fluorophenoxy)-3-methyl-4-nitroisothiazole (Intermediate IIn).

2-(5-Amino-2-chloro-4-fluorophenoxy)pyridine (Intermediate IIo).

15.2

Synthesis of 3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-1) (Process 20).

A solution of triphosgene (0.47 g) in ethyl acetate (10 ml) was stirred under nitrogen while a solution 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (0.45 g) and triethylamine (0.45 ml) in ethyl acetate (15 ml) was added dropwise. The mixture was heated at reflux for 2 hours, cooled, filtered, and the filtrate evaporated to give the corresponding isocyanate.

A suspension of sodium hydride (0.038 g) in N,N-dimethylformamide (2 ml) was stirred at 0° C. under nitrogen while a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (0.26 g) in N,N-dimethylformamide (1 ml) was added dropwise. After 15 minutes a solution of the prepared isocyanate in N,N-dimethylformamide (5 ml) and toluene (5 ml) was added slowly and the solution stirred overnight at room temperature. Dilute hydrochloric acid was added and the solution processed. The resulting solid was chromatographed on silica gel eluting with methanol:methylene chloride, 5:95, to give 3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-1) as a white solid (0.32 g).

The following were similarly prepared:

3-[4-Chloro-2-fluoro-5-(5-bromo-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-2).

3-[4-Chloro-2-fluoro-5-(5-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-3).

3-[4-Chloro-2-fluoro-5-(6-fluoro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-4).

3-[4-Chloro-2-fluoro-5-(6-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-5).

3-[4-Chloro-2-fluoro-5-(3,5,6-trifluoro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-6).

3-[4-Chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-7).

3-[4-Chloro-2-fluoro-5-(4-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-8).

3-[4-Chloro-2-fluoro-5-(3-cyano-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-9).

3-[4-Chloro-2-fluoro-5-(5-cyano-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-10).

3-[4-Chloro-2-fluoro-5-(5 -nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-11).

3-[2,4-Difluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-12).

3-[4-Chloro-2-fluoro-5-(3-ethylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-13).

3-[4-Chloro-2-fluoro-5-(3-methyl-4-nitro-5-isothiazolyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione(Intermediate 11-14).

3-[4-Chloro-2-fluoro-5-(4-chloro-2-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-16).

3-[4-Chloro-2-fluoro-5-(4,6-dimethoxy-2-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-17).

15.3

Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-1) (Process 15).

A suspension of potassium carbonate (0.23 g), 3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.5 g) and 2,4-dinitrophenoxyamine (0.32 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 2:98. The product was isolated as a yellow semi-solid (0.3 g), mp 90-6° C.

The following were similarly prepared:

1-Amino-3-[4-chloro-2-fluoro-5-(5-bromo-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-2).

1-Amino-3-[4-chloro-2-fluoro-5-(5-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-3).

1-Amino-3-[4-chloro-2-fuoro-5-(6-fluoro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-4).

1-Amino-3-[4-chloro-2-fluoro-5-(6-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-5).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5,6-trifluoro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound9-6).

1-Amino-3-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-7).

1-Amino-3-[4-chloro-2-fluoro-5-(4-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-8).

1-Amino-3-[4-chloro-2-fluoro-5-(3-cyano-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-9).

1-Amino-3-[4-chloro-2-fluoro-5-(5-cyano-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-10).

1-Amino-3-[4-chloro-2-fluoro-5-(5-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-11).

1-Amino-3-[2,4-difluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-12).

1-Amino-3-[4-Chloro-2-fluoro-5-(3-ethylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-13).

1-Amino-3-[4-Chloro-2-fluoro-5-(3-methyl-4-nitroisothiazol-5-yloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-14).

1-Amino-3-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-16).

1-Amino-3-[4-chloro-2-fluoro-5-(4-chloro-2-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-17).

1-Amino-3-[4-chloro-2-fluoro-5-(4,6-dimethoxy-2-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-18).

Example 16 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-15) (Process 16).

A solution of triphosgene (0.5 g) in ethyl acetate (10 ml) was stirred under nitrogen while a solution of 2-(5-amino-2-chloro-4-fluorophenoxy)pyridine (0.4 g) and triethylamine (0.5 ml) in ethyl acetate (20 ml) was added dropwise. The mixture was heated at reflux for 2 hours, cooled, filtered, and evaporated to give the corresponding isocyanate.

A suspension of sodium hydride (0.05 g) in N,N-dimethylformamide (2 ml) was stirred at 0° C. under nitrogen while a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (0.32 g) in N,N-dimethylfonnamide (1 ml) was added dropwise. After 15 minutes a solution of the prepared isocyanate in N,N-dimethylformamide (5 ml) and toluene (5 ml) was added slowly. The solution was stirred at room temperature for 2 hours and treated with a solution of 2,4-dinitrophenoxyamine (0.42 g) in N,N-dimethylformamide (4 ml). Stirring was continued for 3 days. The solution was processed and gave a solid which was chromatographed on silica gel cluting with methanol:methylene chloride, 5:95. The title compound was obtained as a yellow solid (0.3 g).

The following were similarly prepared:

1-Amino-3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-1).

1-Amino-3-[4-chloro-2-fluoro-5-(5-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-3).

Example 17 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-21).

17.1

3-[4-Chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-18) (Process 18).

A mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.2 g), 2-chloronitrobenzene (1.3 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours under an atmosphere of nitrogen. The resulting mixture was poured into water (200 ml) and acidified by the addition of a small portion of conc. hydrochloric acid. The solution was extracted with a mixed solvent (ethyl acetate:hexane, 1:1, 400 ml) and the organic phase dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate:hexane, 1:1, to give 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intennediate 11-18) as an amorphous solid (1.0-g).

The following were similarly prepared:

3-[4-Chloro-2-fluoro-5-(3-methylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-19).

3-[4-Chloro-2-fluoro-5-(3-isopropylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-20).

3-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-21)

3-[4-Chloro-2-fluoro-5-(4-nitro-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-22).

3-[4-Chloro-2-fluoro-5-(3-nitro-5-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-23).

3-[4-Chloro-2-fluoro-5-(2-cyanophenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-33).

3-[4-Chloro-2-fluoro-5-(2-cyano-3-fluorophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-34).

17.2

1-Amino-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-21) (Process 15).

A suspension of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (1.0 g), potassium carbonate (0.37 g), and 2,4-dinitrophenoxyamine (0.54 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The solution was processed and the resulting oil was chromatographed on silica gel eluting with methylene chloride:hexane:ethyl acetate, 2:3:0.5. The product was crystallized from methylene chloride:hexane:ethyl acetate to give a white solid (0.45 g).

The following were similarly prepared:

1-Amino-3-[4-chloro-2-fluoro-5-(3-methylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-19).

1-Amino-3-[4-chloro-2-fluoro-5-(3-isopropylsulfonyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-20).

1-Amino-3-[4-chloro-2-fluoro-5-(4-nitro-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-22).

1-Amino-3-[4-chloro-2-fluoro-5-(3-nitro-5-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-23).

1-Amino-3-[4-chloro-2-fluoro-5-(2-cyanophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-30).

1-Amino-3-[4-chloro-2-fluoro-5-(2-cyano-3-fluorophenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-31).

Example 18 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-24).

18.1

3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-24).

A suspension of 10% Pd/C and 3-[4-chloro-2-fluoro-5-(4-nitro-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.0 g) in ethyl acetate (100 ml) was stirred overnight under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrate concentrated. The resulting oil was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:0.8. 3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-24) was isolated as an amorphous solid (3.3 g).

The following were similarly prepared:

3-[4-Chloro-2-fluoro-5-(4-aminophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-25).

3-[4-Chloro-2-fluoro-5-(3-amino-5-trifluoromethylphenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-26).

3-[4-Chloro-2-fluoro-5-(2-aminophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-27).

18.2

3-[4-Chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-28).

3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.0 g) dissolved in anhydrous N,N-dimethylformamide (10 ml) was added to a solution of t-butyl nitrite (1.28 g) in anhydrous N,N-dimethylformamide (40 ml) kept at 60-5° C. under nitrogen. The resulting mixture was stirred for 30 minutes at this temperature. The solution was poured into water and extracted with ethyl acetate: hexane, 1:1, (300 ml). The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2. 3-[4-Chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimid-ine-2,4-dione (Intermediate 11-28) was isolated as an amorphous solid (1.64 g).

The following were similarly prepared:

3-[4-Chloro-2-fluoro-5-(3-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-29).

3-[4-Chloro-2-fluoro-5-phenoxyphenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-30).

18.3

1-Amino-3-[4-chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-24) (Process 15).

A suspension of 3-[4-chloro-2-fluoro-5-(2-trifluoromthylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (0.7 g), potassium carbonate (0.27 g) and 2,4-dinitrophenoxyamine (0.39 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 72 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 4:1, containing 0.1% of triethylamine. The product (Compound 9-24) was isolated as a pale yellow amorphous solid (0.6 g).

The following were similarly prepared:

1-Amino-3-[4-chloro-2-fluoro-5-(3-trifluoromethylphenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-25).

1-Amino-3-[4-chloro-2-fluoro-5-phenoxyphenyl -6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-26).

Example 19 Synthesis of ethyl 2-[4-[2-chloro-4-fluoro-5-(1-amino-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dion-3yl)phenoxy]phenoxy]propionate (Compound 9-27).

19.1

3-[4-Chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-31).

3-[4-Chloro-2-fluoro-5-(4-aminophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (2.0 g) was mixed with hot 30% sulfuric acid (5 ml) and ic/water (5.0 g) was added. The mixture kept at 10° C. while a solution of sodium nitrite (0.45 g) in water (5 ml) was slowly introduced at the bottom of the stirred mixture. After stirring for 10 minutes, urea (0.1 g) was added, followed by a solution of copper(2)nitrate (18.0 g) in water (170 ml), and copper(1)oxide (0.7 g). The mixture was stirred for 10 minutes, extracted with diethyl ether (50 ml×3), and dried over sodium sulfate. The crude product was purified by column chromatography (hexane:ethyl acetate, 4:1) to give 3-[4-chloro -2-fluoro-5-(4-hydroxyphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-31), (1.0 g).

19.2

Ethyl 2-[4-[2-chloro-4-fluoro-5-(6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dion-3yl)phenoxy]phenoxy]propionate (Intermediate 11-32).

A solution of 3-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (1.0 g) in butan-2-one (20 ml) was mixed with ethyl 2-bromopropionate (1 equivalent) and potassium carbonate (1 equivalent) and heated at reflux for 4 hours. The mixture was filtered and evaporated. The crude product was chromatographed to give ethyl 2-[4-[2-chloro-4-fluoro-5-(6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dion-3-yl)phenoxy]phenoxy]propionate (Intermediate 11-32) (0.81 g).

19.3

Ethyl 2-[4-[2-chloro-4-fluoro-5-(1-amino-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dion-3yl)phenoxy]phenoxy]propionate (Compound 9-27) (Process 15).

A suspension of ethyl 2-[4-[2-chloro4-fluoro-5-(4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dion-3yl)phenoxy]phenoxy]propionate (0.81 g), potassium carbonate (0.24 g) and 2,4-dinitrophenoxyamine (0.35 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 24 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with hexane ethyl acetate, 4:1. The product, ethyl 2-[4-[2-chloro-4-fluoro-5-(1-amino-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dion-3-yl)phenoxy]phenoxy]propionate (Compound 9-27) was isolated as a pale yellow amorphous solid (0.51 g).

Example 20 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(5-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydro-2-oxo-4-thioxopyrimidine (Compound 9-28) (Process 17).

A mixture of 1-amino-3-[4-chloro-2-fluoro-5-(5-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.27 g), sodium bicarbonate (0.19 g) and Lawessons' reagent (0.26 g) in dry toluene (10 ml) was heated at reflux for 4 hours. The mixture was cooled, filtered, and the residue evaporated under reduced pressure. The resulting oil was chromatographed on silica gel eluting with ethyl acetate:hexane, 4:6, to give a yellow viscous oil (0.18 g).

The following were similarly prepared.

1-Amino-3-[4-chloro-2-fluoro-5(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2-oxo-4-thioxopyrimidine (Compound 9-29).

Example 21 Synthesis of 1-amino-3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-1).

21.1

1-Amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione.

A suspension of sodium hydride (1.0 g, 60% in oil) in N,N-dimethylformamide (30 ml) was stirred at 0° C. under nitrogen while a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (4.5 g) in N,N-dimethylformamide (20 ml) was added dropwise. After stirring for 15 minutes, a solution of 4-chloro-2-fluoro-5-isopropyloxyphenylisocyanate (5.6 g) in toluene (25 ml) was added slowly at −35° C. The solution was stirred at room temperature for 2 hours and treated with a solution of 2,4-dinitrophenoxyamine (5.8 g) in N,N-dimethylformamide (20 ml). Stirring was continued for 3 days. The solution was processed and gave a solid which was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:5, containing 0.1% of triethylamine. 1-Amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione was obtained as a white solid (5.3 g).

21.2

1-Amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione.

Conc. sulfuric acid (3 ml) was added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.5 g) in methylene chloride (50 ml) stirred at 0° C. . After 1 hour the mixture was diluted with water and processed. The oily product was chromatographed on silica gel eluting with ethyl acetate:hexane, 2:3, to give 1-amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione as a pale yellow amorphous solid (3.6 g,). ¹H NMR (CDCl₃, TMS): 7.27(1H, d, J=8.8 Hz), 6.88(1H, d, J=6.5 Hz), 6.28(1H, s), 5.86(1H, br. s), 4.61(2H, s)

21.3

1-Amino-3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-1) (Process 14).

Sodium hydride (75 mg, 60% in oil) was added at room temperature to a mixture of 1-amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.5 g) and 2-chloro-3-nitropyridine (0.35 g) in anhydrous tetrahydrofuran (50 ml). After stirring for 36 hours water was added and the reaction mixture processed. Chromatography on silica gel eluting with ethyl acetate:hexane, 1:2, gave compound 9-1 as a yellow semi-solid (0.1 g).

The following compounds may be similarly prepared:

1-Amino-3-[4-chloro-2-fluoro-5-(5-trifuoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-32).

1-Amino-3-[2,4-dichloro-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-33).

1-Amino-3-[2,4-difluoro-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-34).

1-Amino-3-[4-chloro-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-35).

1-Amino-3-[4-bromo-2-fluoro-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-36).

1-Amino-3-[4-bromo-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-37).

1-Amino-3-[4-chloro-2-fluoro-5-(3-amino-2-pyridyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-38).

1-Amino-3-[4-chloro-2-fluoro-5-(3-aminotrifluoroacetyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-39).

1-Amino-3-[4-chloro-2-fluoro-5-(3-aminoacetyl-2-pyridyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-40).

1-Amino-3-[4-chloro-2-fluoro-5-(3-aminomethylsulfonate-2-pyridyloxy)phenyl]6-trifluoromethyl-1,2,3,4-tetrabydropyrimidine-2,4-dione (Compound 9-41).

1-Amino-3-[4-chloro-2-fluoro-5-(3-chloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-42).

1-3-[4-chloro-2-fluoro-5-(6-bromo-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-43).

1-Amino-3-[4-chloro-2-fluoro-5-(5-chloro-3-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-44).

1-Amino-3-[4-chloro-2-fluoro-5-(3-nitro-5-trifluoromethyl-2-pyridyloxy)phenyl]6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-45).

1-Amino-3-4-chloro-2-fluoro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrabydropyrimidine-2,4-dione (Compound 9-46).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5-dichloro-2-pyridyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-47).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5-dinitro-2-pyridyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-48).

1-Amino-3-[4-chloro-2-fluoro-5-(4,6-bistrifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-49).

1-Amino-3-[4-chloro-2-fluoro-5-(6-chloro-4-cyano-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-50).

1-Amino-3-[4-chloro-2-fluoro-5-(4,5-bistrifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-51).

1-Amino-3-[4-chloro-2-fluoro-5-(3,6-bistrifluoromethyl-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-52).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5,6-trichloro-4-trifluoromethyl-2-pyridyloxy)-phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-53).

1-Amino-3-[4-chloro-2-fluoro-5-(3,4,5-trichloro-6-trifluoromethyl-2-pyridyloxy)-phenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (Compound 9-54).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5-dichloro-4,6-difluoro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-55).

1-Amino-3-[4-chloro-2-fluoro-5-(3,5,6-trifluoro-4-bromo-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-56).

1-Amino-3-[4-chloro-2-fluoro-5-(3,4,5,6-tetrachloro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-57).

1-Amino-3-[4-chloro-2-fluoro-5-(5-bromo-2-pyrimidyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-58).

1-Amino-3-[4-chloro-2-fluoro-5-(6-chloro-5-nitro-4-pyrimidyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-59).

1-Amino-3-[4-chloro-2-fluoro-5-(6-chloro-2-pyridazinyloxy)phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-60).

1-Amino-3-[4-chloro-2-fluoro-5-(2-chloro-6-nitrophenoxy)phenyl]-6 -trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-61).

1-Amino-3-[4-chloro-2-fluoro-5-(4-fluoro-6-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-62).

1-Amino-3-[4-chloro-2-fluoro-5-(3-fluoro-6-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-63).

1-Amino-3-[4-chloro-2-fluoro-5-(3-fluoro-2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-64).

1-Amino-3-[4-chloro-2-fluoro-5-(2-fluorophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-trahydropyrimidine-2,4-dione (Compound 9-65).

1-Amino-3-[4-chloro-2-fluoro-5-(3-fluorophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-66).

1-Amino-3-[4-chloro-2-fluoro-5-(4-fluorophenoxy)phenyl]-6-trifuoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-67).

1-Amino-3-[4-chloro-2-fluoro-5-(2-chloro-4-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-68).

1-Amino-3-[4-chloro-2-fluoro-5(4-cyano-2,3,5,6-tetrafluorophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-69).

1-Amino-3-[4-chloro-2-fluoro-5-(3-chloro-4,6-dinitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-70).

1-Amino-3-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-71).

1-Amino-3-[4-chloro-2-fluoro-5-(6-chloro-3-pyridazinyloxy)-phenyl]-6-trifluoro-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Compound 9-72).

Some of the compounds of the present invention produced by the methods described above are shown in Tables 1-9. The physical data on intermediates including the NMR data is shown in Tables 10 and 11. The NMR data of compounds of the present invention are shown in Table 12.

TABLE 1 Examples of formula (I) Com- pound Q₁ Physical No. Ar X Y Z R₁ R₂ R₃ Properties 1-1 3-nitro-2- F Cl O Cl CF₃ CH₃ pyridyl 1-2 3-trifluoro- F Cl O Cl CF₃ CH₃ methyl-2- pyridyl 1-3 3-cyano-2- F Cl O Cl CF₃ CH₃ pyridyl 1-4 5-cyano-2- F Cl O Cl CF₃ CH₃ pyridyl 1-5 6-fluoro-2- F Cl O Cl CF₃ CH₃ pyridyl 1-6 3,5,6-trifluoro- F Cl O Cl CF₃ CH₃ 2-pyridyl 1-7 2-pyrimidyl F Cl O Cl CF₃ CH₃ 1-8 4,6-dimethoxy- F Cl O Cl CF₃ CH₃ 2-triazinyl 1-9 phenyl CN NO₂ S Br CH₃ C₂H₅

TABLE 2 Examples of formula (I) Compound Q₂ Physical No. Ar X Y Z R₁ R₂ R₃ Properties 2-1 3-nitro-2- F Cl O Cl CF₃ CH₃ pyridyl 2-2 3-trifluoromethyl- F Cl O Cl CF₃ CH₃ 2-pyridyl 2-3 2-pyrimidyl F Cl O Cl CF₃ CH₃ 2-4 4,6-dimethoxy- F Cl O Cl CHF₂ CH₃ 2-triazinyl 2-5 2-nitrophenyl CF₃ F S Br C₂H₅ n-C₃H₇

TABLE 3 Examples of formula (I) Compound Q₃ Physical No. Ar X Y Z R₂ R₃ Properties 3-1 2-pyrimidyl F Cl O CH₃ CHF₂

TABLE 4 Examples of formula (I) Compound Q₄ Physical No. Ar X Y Z R₃ R₅ R₄ Properties 4-1 3-trifluoromethyl- F Cl O H CH₃ CH₃ 2-pyridyl 4-2 3-trifluoromethyl- F Cl O —CH₂CH₂CH₂— H 2-pyridyl 4-3 phenyl NO₂ CF₃ S —CH₂CH₂— C₂H₅

TABLE 5 Examples of formula (I) Compound Physical No. Ar X Y Z Q₅ Properties 5-1 2-nitrophenyl F Cl O Q₅ 5-2 4-nitrophenyl F Cl O Q₅ 5-3 4-aminophenyl F Cl O Q₅ 5-4 4-hydroxy- F Cl O Q₅ phenyl 5-5 4-methyl- F Cl O Q₅ sulfonyl- aminophenyl 5-6 4-(1-ethoxycar- F Cl O Q₅ bonylethoxy) phenyl 5-7 3-chloro-2- F Cl O Q₅ 5-8 3-nitro-2-pyridyl F Cl O Q₅ 5-9 3-cyano-2 F Cl O Q₅ pyridyl 5-10 3-trifluoro- F Cl O Q₅ methyl-2-pyridyl 5-11 5-cyano-2 F Cl O Q₅ pyridyl 5-12 2-pyrimidyl F Cl O Q₅ 5-13 5-nitro-2 CF₃ NO₂ S Q₅ thiazolyl 5-14 3-methyl-4- CN H S Q₅ cyano-5- isothiazolyl

TABLE 6 Examples of formula (I) Com- pound Q₆ Physical No. Ar X Y Z R₆ Properties 6-1 2-pyridyl F Cl O CH₂CH₂CH₂F 6-2 3-nitro-2-pyridyl F Cl O CH₂CH₂CH₂F 6-3 3-nitro-2-pyridyl Cl Cl O CH₂CH₂CH₂F 6-4 3-cyano-2- F Cl O CH₂CH₂CH₂F pyridyl 6-5 3-cyano-2- Cl Cl O CH₂CH₂CH₂F pyridyl 6-6 3-trifluorome- F Cl O CH₂CH₂CH₂F thyl-2-pyridyl 6-7 3-trifluorome- Cl Cl O CH₂CH₂CH₂F thyl-2-pyridyl 6-8 5-trifluorome- F Cl O CH₂CH₂CH₂F thyl-2-pyridyl 6-9 5-trifluorome- Cl Cl O CH₂CH₂CH₂F thyl-2-pyridyl 6-10 2-pyrimidyl F Cl O CH₂CH₂CH₂F m.p. 111- 3° C. 6-11 2-pyrimidyl F Cl O CH₂CH₃ 6-12 2-pyrimidyl F Cl O CH₂CH₂OCH₃ 6-13 2-pyrimidyl F Cl O CH₂CH₂CN 6-14 2-pyrimidyl Cl Cl O CH₂CH₂CH₂F 6-15 4-6-dimethoxy- F Cl O CH₂CH₂CH₂F 2-pyrimidyl 6-16 5-bromo-2- F Cl O CH₂CH₂CH₂F pyrimidyl 6-17 3-methyl-4- F Cl O CH₂CH₂CH₂F nitro-5- isothiazolyl 6-18 phenyl Cl F S CH₂C≡CBr

TABLE 7 Examples of formula (I) Compound Physical No. Ar X Y Z Q₅ Properties 7-1 3-trifluoro- F Cl O Q₇ methyl-2-pyridyl 7-2 2-pyrimidyl F Cl O Q₇ 7-3 phenyl CN NO₂ S Q₇

TABLE 8 Examples of formula (I) Compound Q₈ Physical No. Ar X Y Z A₁ A₂ B R₇ R₈ Properties 8-1  3-trifluoromethyl- F Cl O O O CH CH₂CH₃ H 2-pyridyl 8-2  2-pyrimidyl F Cl O O O CH CH₂CH₃ H 8-3  2-pyrimidyl F Cl O O O CH CH₃ H 8-4  3-trifluoromethyl- F Cl O O O CH —(CH₂)₄— 2-pyridyl 8-5  phenyl F Cl O S O N —(CH₂)₄— 8-6  2-nitrophenyl F Cl O S O N —(CH₂)₄— 8-7  2-cyanophenyl F Cl O S O N —(CH₂)₄— 8-8  4-nitrophenyl F Cl O S O N —(CH₂)₄— 8-9  4-aminophenyl F Cl O S O N —(CH₂)₄— 8-10 4-hydroxy- F Cl O S O N —(CH₂)₄— phenyl 8-11 4-(1-ethoxycar- F Cl O S O N —(CH₂)₄— bonylethoxy)- phenyl 8-12 2-cyano-4- F Cl O S O N —(CH₂)₄— nitrophenyl 8-13 4-amino-2- F Cl O S O N —(CH₂)₄— cyanophenyl 8-14 4-nitro-2- F Cl O S O N —(CH₂)₄— trifluoromethyl phenyl 8-15 4-amino-2- F Cl O S O N —(CH₂)₄— trifluoromethyl phenyl 8-16 4-acetylamino- F Cl O S O N —(CH₂)₄— 2-trifluoro- methylphenyl 8-17 2-pyridyl F Cl O S O N —(CH₂)₄— 8-18 3-trifluoromethyl- F Cl O S O N —(CH₂)₄— 2-pyridyl 8-19 3-nitro-2- F Cl O S O N —(CH₂)₄— pyridyl 8-20 3-cyano-2- F Cl O S O N —(CH₂)₄— pyridyl 8-21 3-methylsulfonyl- F Cl O S O N —(CH₂)₄— 2-pyridyl 8-22 5-cyano-2- F Cl O S O N —(CH₂)₄— pyridyl 8-23 5-nitro-2- F Cl O S O N —(CH₂)₄— pyridyl 8-24 5-amino-2- F Cl O S O N —(CH₂)₄— pyridyl 8-25 6-fluoro-2- F Cl O S O N —(CH₂)₄— pyridyl 8-26 6-chloro-2- F Cl O S O N —(CH₂)₄— pyridyl 8-27 3-trifluoromethyl- F Cl O S O N —(CH₂)₄— 6-chloro- 2-pyridyl 8-28 3,5,6-trifluoro- F Cl O S O N —(CH₂)₄— 2-pyridyl 8-29 2-pyrimidyl F Cl O S O N —(CH₂)₄— 8-30 4-trifluoromethyl- F Cl O S O N —(CH₂)₄— 2-pyrimidyl 8-31 4-chloro-2- F Cl O S O N —(CH₂)₄— pyrimidyl 8-32 2,6-dimethoxy- F Cl O S O N —(CH₂)₄— 4-pyrimidyl 8-33 4,6-dimethoxy- F Cl O S O N —(CH₂)₄— 2-pyrimidyl 8-34 4,6-dimethoxy- F Cl O S O N —(CH₂)₄— 2-triazinyl 8-35 3-methyl-4- F Cl O S O N —(CH₂)₄— nitro-5- isothiazolyl 8-36 5-nitro-2- F Cl O S O N —(CH₂)₄— thiazolyl 8-37 3-isopropylsul- F Cl O S O N —(CH₂)₄— fonyl-2-pyridyl 8-38 5-chloro-4-(1- F Cl O S O N —(CH₂)₄— ethoxycar- bonylethoxy)- 2-nitrophenyl 8-39 4-(1-ethoxycar- F Cl O S O N —(CH₂)₄— bonylethoxy)- 2-nitrophenyl 8-40 2-amino-4-(1- F Cl O S O N —(CH₂)₄— ethoxycar- bonylethoxy)- phenyl 8-41 4-(1-ethoxycar- F Cl O S O N —(CH₂)₄— bonylethoxy)- 2-nitrophenyl 8-42 3-amino-2- F Cl O S O N —(CH₂)₄— pyridyl 8-43 3-methylthio-2- F Cl O S O N —(CH₂)₄— pyridyl 8-44 3-dimethyl- Br Cl S O O N —(CH₂)₃— aminocarbonyl- 2-pyridyl 8-45 2-pyrimidyl NO₂ CF₃ S O O N —(CH₂)₃— 8-46 phenyl CF₃ CN S O O N C₂H₅ C₂H₅ 8-47 2-pyrimidyl F Cl O S O CH —(CH₂)₄— (R, S) 8-48 2-pyrimidyl F Cl O O O CH —(CH₂)₄— (R, S) 8-49 2-pyrimidyl F Cl O S O CH —(CH₂)₄— (S) 8-50 2-pyrimidyl F Cl O S O CH —(CH₂)₄— (S) 8-51 phenyl F Cl O S O CH —(CH₂)₄— (R, S) 8-52 2-nitrophenyl F Cl O S O CH —(CH₂)₄— (R, S) 8-53 2-cyanophenyl F Cl O S O CH —(CH₂)₄— (R, S) 8-54 2-pyrazinyl F Cl O S O CH —(CH₂)₄— (R, S) 8-55 2-pyridyl F Cl O S O CH —(CH₂)₄— (R, S) 8-56 3-chloro-2- F Cl O S O CH —(CH₂)₄— (R, S) pyridyl 8-57 3-chloro-2-tri- F Cl O S O CH —(CH₂)₄— (R, S) fluoromethyl- 2-pyridyl 8-58 3-trifluoro- F Cl O S O CH —(CH₂)₄— (R, S) methyl-2- pyridyl 8-59 3-nitro-2- F Cl O S O CH —(CH₂)₄— (R, S) pyridyl 8-60 3-cyano-2- F Cl O S O CH —(CH₂)₄— (R, S) pyridyl 8-61 3-amino-2- F Cl O S O CH —(CH₂)₄— (R, S) pyridyl 8-62 2-aminophenyl F Cl O S O CH —(CH₂)₄— (R, S) 8-63 3-acetylamino- F Cl O S O CH —(CH₂)₄— (R, S) 2-pyridyl 8-64 2-(bisbenzoyl)- F Cl O S O CH —(CH₂)₄— (R, S) aminophenyl

TABLE 9 Examples of Formula (1). (Q₉)

Compd. Q₉ Physical No. Ar X Y Z A₁ A₂ R₉ R₁₀ property 9-1 3-nitro-2-pyridyl F Cl O O O H H mp 90-96 9-2 5-bromo-2-pyridyl F Cl O O O H H mp 69-70 9-3 5-chloro-2-pyridyl F Cl O O O H H amorphous 9-4 6-fluoro-2-pyridyl F Cl O O O H H amorphous 9-5 6-chloro-2-pyridyl F Cl O O O H H amorphous 9-6 3,5,6-trifluoro-2-pyridyl F Cl O O O H H amorphous 9-7 3-trifluoromethyl-2-pyridyl F Cl O O O H H amorphous 9-8 4-trifluoromethyl-2-pyridyl F Cl O O O H H amorphous 9-9 3-cyano-2-pyridyl F Cl O O O H H amorphous 9-10 5-cyano-2-pyridyl F Cl O O O H H amorphous 9-11 5-nitro-2-pyridyl F Cl O O O H H amorphous 9-12 3-trifluoromethyl-2-pyridyl F F O O O H H amorphous 9-13 3-ethylsulfonyl-2-pyridyl F Cl O O O H H mp 277-279 9-14 3-methyl-4-nitro-5-isothiazolyl F Cl O O O H H amorphous 9-15 2-pyridyl F Cl O O O H H amorphous 9-16 2-pyrimidyl F Cl O O O H H white solid 9-17 4-chloro-2-pyrimidyl F Cl O O O H H amorphous 9-18 4,6-dimethoxy-2-pyrimidyl F Cl O O O H H amorphous 9-19 3-methylsulfonyl-2-pyridyl F Cl O O O H H mp 276-278 9-20 3-isopropylsulfonyl-2-pyridyl F Cl O O O H H mp 155-158 9-21 2-nitrophenyl F Cl O O O H H mp 155-158 9-22 4-nitro-2-trifluoromethylphenyl F Cl O O O H H amorphous 9-23 3-nitro-5-trifluoromethylphenyl F Cl O O O H H amorphous 9-24 2-trifluoromethylphenyl F Cl O O O H H amorphous 9-25 3-trifluoromethylphenyl F Cl O O O H H amorphous 9-26 phenyl F Cl O O O H H amorphous 9-27 4-(1-ethoxycarbonylethoxy)- F Cl O O O H H amorphous phenyl 9-28 5-chloro-2-pyridyl F Cl O S O H H amorphous 9-29 3-nitro-2-pyridyl F Cl O S O H H amorphous 9-30 2-cyanophenyl F Cl O O O H H mp 220-222 9-31 2-cyano-3-fluorophenyl F Cl O O O H H mp 230-233 9-32 5-trifluoromethyl-2-pyridyl F Cl O O O H H 9-33 5-trifluoromethyl-2-pyridyl Cl Cl O O O H H 9-34 5-trifluoromethyl-2-pyridyl F F O O O H H 9-35 5-trifluoromethyl-2-pyridyl H Cl O O O H H 9-36 5-trifluoromethyl-2-pyridyl F Br O O O H H 9-37 5-trifluoromethyl-2-pyridyl H Br O O O H H 9-38 3-amino-2-pyridyl F Cl O O O H H 9-39 3-aminotrifluoroacetyl-2-pyridyl F Cl O O O H H 9-40 3-aminoacetyl-2-pyridyl F Cl O O O H H 9-41 3-aminomethylsulfonate-2- F Cl O O O H H pyridyl 9-42 3-chloro-2-pyridyl F Cl O O O H H 9-43 6-bromo-2-pyridyl F Cl O O O H H 9-44 5-chloro-3-trifluoromethyl- F Cl O O O H H 2-pyridyl 9-45 3-nitro-5-trifluoromethyl-2- F Cl O O O H H pyridyl 9-46 3-chloro-5-trifluoromethyl- F Cl O O O H H 2-pyridyl 9-47 3,5-dichloro-2-pyridyl F Cl O O O H H 9-48 3,5-dinitro-2-pyridyl F Cl O O O H H 9-49 4,6-bistrifluoromethyl-2-pyridyl F Cl O O O H H 9-50 6-chloro-4-cyano- F Cl O O O H H 2-pyridyl 9-51 4,5-bistrifluoromethyl-2-pyridyl F Cl O O O H H 9-52 3,6-bistrifluoromethyl-2-pyridyl F Cl O O O H H 9-53 3,5,6-trichloro-4-trifluoromethyl- F Cl O O O H H 2-pyridyl 9-54 3,4,5-trichloro-6-trifluoromethyl- F Cl O O O H H 2-pyridyl 9-55 1,3,5-dichloro-4,6-difluoro- F Cl O O O H H 2-pyridyl 9-56 4-bromo-3,5,6-trifluoro-2-pyridyl F Cl O O O H H 9-57 3,4,5,6-tetrachloro-2-pyridyl F Cl O O O H H 9-58 5-bromo-2-pyrimidyl F Cl O O O H H 9-59 6-chloro-5-nitro-4-pyrimidyl F Cl O O O H H 9-60 6-chloro-4-pyridazinyl F Cl O O O H H 9-61 2-chloro-6-nitrophenyl F Cl O O O H H 9-62 4-fluoro-6-nitrophenyl F Cl O O O H H 9-63 3-fluoro-6-nitrophenyl F Cl O O O H H 9-64 3-fluoro-2-nitrophenyl F Cl O O O H H 9-65 2-fluorophenyl F Cl O O O H H 9-66 3-fluorophenyl F Cl O O O H H 9-67 4-fluorophenyl F Cl O O O H H 9-68 2-chloro-4-nitrophenyl F Cl O O H H 9-69 4-cyano-2,3,5,6-tetrafluoro- F Cl O O O H H phenyl 9-70 3-chloro-4,6-dinitrophenyl F Cl O O O H H 9-71 4-nitrophenyl F Cl O O O H H 9-72 6-chloro-3-pyridazinyl F Cl O O O H H

TABLE 10 Examples of Intermediate (II), (III), and (XX) Inter- mediate Physical No. Ar Y X Z property ¹H NMR (CDCl₃) IIa 3-nitro-2- Cl F O amorphous 3.93(2H, s), 6.67(1H, d, J=8.2Hz), 7.08(1H, d, pyridyl J=10.5Hz), 7.18(1H, dd, J=7.9, 4.8Hz), 8.31(1H, dd, J=4.8, 1.8Hz), 8.38(1H, dd, J=7.9, 1.8Hz). IIb 5-bromo-2- Cl F O brown 3,80(2H, br s), 6.62(1H, d, J=7.Hz), 6.87(1H, d, pyridyl solid J=8.7Hz), 7.71(1H, d, J=10.4Hz), 7.77(1H, dd, J=8.7, 2.5Hz), 8.18(1H, d, J=2.5Hz). IIc 5-chloro-2- Cl F O colorless 3.83(2H, br s), 5.61(1H, d, J=8.3Hz), 6.90(1H, d, pyridyl crystals J=8.7Hz), 7.10(1H, d, J=10.4Hz), 7.64(1H, m), 808(1H, m). IId 6-fluoro-2- Cl F O amorphous 3.81(2H, br s), 6.60(1H, dd, J=2.7, 8.0Hz), pyridyl 6.63(1H, d, J=8.2Hz), 6.75(1H, dd, J=1.2, 7.7 Hz), 7.09(1H, d, J=10.4Hz), 7.76(1H, dd, J=8.0, 15.9Hz). IIe 6-chloro-2- Cl F O mp 3.80(2H, br s), 6.64(1H, d, J=8.3Hz), 6.77(1H, d, pyridyl 114-116 J=8.1Hz), 7.05(2H, m), 7.61(1H, m). IIf 3, 5, 6-tri- Cl F O amorphous 3.83(2H, br s), 6.64(1H, d, J=8.1Hz), 7.10(1H, d, fluoro-2- J=10.2Hz), 7.51(1H, m). pyridyl IIg 3-trifluoro- Cl F O crystals 3.78(2H, br), 6.64(1H, d, J=8.2Hz), 7.09(1H, m), methyl-2- 7.09(1H, d, J=10.3Hz), 7.99(1H, m), 8.26(1H, pyridyl m). IIh 4-trifluoro- Cl F O mp 3.83(2H, m), 6.64(1H, d, J=8.2Hz), 7.12(1H, d, methyl-2- 73-74 J=10.3Hz), 7.20(2H, m), 8.29(1H, d, J=5.2Hz); pyridyl IIi 3-cyano-2- Cl F O amorphous 3.85(2H, br s), 6.69(1H, d, J=8.2Hz), 7.12(1H, pyridyl dd, J=7.6, 5.0Hz), 7.12(1H, d, J=10.9Hz), 8.02(1H, dd, J=1.9, 7.6Hz), 8.31(1H, dd, J=1.9, 5.0Hz). IIj 5-cyano-2- Cl F O amorphous 3.69(2H, br s), 6.67(1H, d, J=8.2Hz), 7.07(1H, d, pyridyl J=8.6Hz), 7.12(1H, d, J=10.4Hz), 7.98(1H, dd, J=2.3, 8.7Hz), 8.45(1H, d, J=2.3Hz). IIk 5-nitro-2- Cl F O amorphous 3.89(2H, br s), 6.65(1H, d, J=8.2Hz), 7.08(1H, d, pyridyl J=9.5Hz), 7.13(1H, d, J=10.4Hz), 8.50(1H, dd, J=2,8, 9.0Hz), 9.02(1H, d, J=2.8Hz). IIl 3-trifluoro- F F O amorphous 3.65(2H, br s), 6.66(1H, dd, J=8.6, 7.6Hz), methyl-2- 6.90(1H, dd, J=10.1, 10.1Hz), 7.10(1H, m), pyridyl 7.98(1H, m), 8.27(1H, m). IIm 3-ethyl- Cl F O mp 1.33(3H, t), 3.56(2H, q), 3.88(2H, br s), 6.72(1H, sulfonyl-2- 189˜191 d) 7.10˜7.27(2H, m), 8.31˜8.39(2H, m). pyridyl IIn 3-methyl-4- Cl F O amorphous 2.68(3H, s), 4.11(2H, br s), 6.79(1H, d, J=8.0 nitro-5- Hz), 7.15(1H, d, J=10.2Hz). isothiazolyl IIo 2-pyridyl Cl F O mp 3.82(2H, br s), 6.62(1H, s), 6.98(2H, m), 124-126 7.10(1H, d, J=10.5Hz), 7.69(1H, m), 8.15(1H, m). IIp 2- Cl F O yellow 4.75(2H, br s), 6.78(1H, d, J=8.4Hz), 7.09(1H, d, pyrimidyl crystals J=10.6Hz), 7.15(1H, t, J=4.8Hz), 8.56(2H, d, J=4.8Hz). IIq 4-chloro-2- Cl F O amorphous 5.61(2H, br s), 6.82(1H, d, J=5.7Hz), 6.84(1H, d, pyrimidyl J=8.2Hz), 7.08(1H, d, J=10.5Hz), 8.42(1H, d, J=5.7Hz). IIr 4-6-dime- Cl F O amorphous 3.81(6H, s), 5.77(1H, s), 6.67(1H, d, J=8.4Hz), thoxy-2- 7.06(1H, d, J=10.4Hz). pyrimidyl IIs 4-chloro-2- Cl Cl O 6.69(1H, s), 7.34(1H, s), 7.08(1H, t, J=4.8Hz), pyrimidyl 8.56(1H, d, J=4.8Hz). IIt 2-nitro- Cl F O 3.85(2H, br s), 6.55(1H, d, J=8.4Hz), 6.82(1H, phenyl dd, J=8.5, 1.0Hz), 7.12(1H, dd, J=10.4, 1.0Hz), 7.17(1H, ddd, J=8.2, 7.4, 1.2Hz), 7.48(1H, ddd, J=8.5, 7.4, 1.7Hz), 7.96(1H, dd, J=8.1, 1.7Hz). IIIc 2- Cl F O 7.03(1H, d, J=7.2Hz), 7.10(1H, t, J=4.8Hz), pyrimidyl 7.31(1H, d, J=8.9Hz), 8.57(1H, d, J=4.8Hz), IIId 3-trifluoro- Cl F O 7.02(1H, d, J=7.3Hz), 7.14(1H, dd, 6.9, 5.0Hz,), methyl-2- 7.31(1H, d, J=8.9Hz), 8.02(1H, d, J=6.9Hz), pyrimidyl 8.25(1H, d, J=5.0Hz). XX 3-trifluoro- Cl F O 7.12(1H, d, J=6.9Hz), 7.16(1H, m), 7.31(1H, d, methyl-2- J=8.9Hz), 8.03(1H, m), 8.24(1H, m). pyridyl

TABLE 11 Examples of Intermediates (XXXV) (XXXV)

Intermediate Physical No. Ar X Y property ¹H NMR (CDCl₃) 11-1 3-nitro-2- F Cl mp 1.55(1H, br s), 6.24(1H, s), 7.23(2H, m), 7.43(1H, d, pyridyl 220-223 J = 7.9 Hz), 8.33(1H, m), 8.43(1H, m). 11-2 5-bromo- F Cl amorphous 3.30(1H, br), 6.21(1H, s), 6.92(1H, m), 7.20(1H, d, 2-pyridyl J = 6.7 Hz), 7.38(1H, d, J = 9.0 Hz), 7.81(1H, m), 8.13(1H, m). 11-3 5-chloro-2- F Cl oil 6.19(1H, s), 6.96(1H, d, J = 8.7 Hz), 7.20(1H, d J = 6.7 pyridyl Hz), 7.37(1H, d, J = 8.9 Hz), 7.68(1H, dd, J = 8,7,2.6 Hz), 8.03(1H, d, J = 2.6 Hz). 11-4 6-fluoro-2- F Cl amorphous 6.22(1H, s), 6.64(1H, dd, J = 2.5, 8.0 Hz), 6.81(1H d, pyridyl J = 8.0 Hz), 7.21(1H, d, J = 6.7 Hz), 7.38(1H, d, J = 9.0 Hz), 7.79(1H, d, J = 7.9, 15.8 Hz). 11-5 6-chloro-2- F Cl amorphous 6.17(1H, s), 6.80(1H, m), 7.04(1H, m), 7.20(1H, m), pyridyl 7.35(1H, m), 7.63(1H, m). 11-6 3,5,6-tri- F Cl amorphous 6.22(1H, s), 7.23(1H, d, J = 6.6 Hz), 7.40(1H, d, J = 8.9 fluoro-2- Hz), 7.54(1H, m), 8.04(1H, br s). pyridyl 11-7 3-trifluoro- F Cl amorphous (acetone-d₆-CDCl₃) 6.22(1H, s), 7.20(1H, m), methyl-2- 7.36(1H, d, J = 6.7 Hz), 7.42(1H, d, J = 9.0 Hz), pyridyl 8.06(1H, m), 8.24(1H, m). 11-8 4-trifluoro- F Cl amorphous 6.22(1H, s), 7.23(3H, Hz), 7.40(1H, J = 9.0 Hz), methyl-2- 8.25(1H, d, J = 5.1 Hz). pyridyl 11-9 3-cyano-2- F Cl amorphous 6.22(1H, s), 7.16(1H, dd, J = 5.0, 7.5 Hz), 7.27(1H, d, pyridyl J = 6.6 Hz), 7.40(1H, d, J = 9.0 Hz), 8.05(1H, dd, J = 1.9, 7.5 Hz), 8.27(1H, dd, J = 1.9, 5.0 Hz). 11-10 5-cyano-2- F Cl amorphous 6.23(1H, s), 7.12(1H, d, J = 8.6 Hz), 7.21(1H, d, J = 6.6 pyridyl Hz), 7.41(1H, d, J = 8.9 Hz), 7.97(1H, dd, J = 2.3, 8.6 Hz) 8.41(1H, d, J = 2.3 Hz). 11-11 5-nitro-2- F Cl amorphous (CDCl₃ + CD₃OD) 6.21(1H, s), 7.16(1H, d, J = 9.1 Hz), pyridyl 7.27(1H, d, J = 6.6 Hz), 7.45(1H, d, J = 8.8 Hz), 8.55(1H, dd, J = 2.8, 9.0 Hz), 8.99(1H, d, J = 2.7 Hz). 11-12 3-trifluoro- F F amorphous 6.2(1H, s), 7.11(1H, m), 7.14(1H,m), 7.23(1H, m), methyl-2- 7.99(1H, d, J = 7.6 Hz), 8.23(1H, d, J = 5.0 Hz). pyridyl 11-13 3-ethyl- F Cl amorphous 1.32(3H, t), 3.57(2H, q), 6.24(1H, s), 7.26(2H, d), sulfonyl-2- 7.42(1H,d), 8.30(1H, d), 8.37(1H, d), pyridyl 10.20(1H, br s). 11-14 3-methyl-4- F Cl amorphous 2.70(3H, s), 6.27(1H, s), 7.39(1H, d, J = 6.4 Hz), nitro-5- 7.51(1H, d, J = 8.6 Hz). isothiazolyl 11-15 2-pyrimidyl F Cl amorphous 6.22(1H, s), 7.18(1H, t, J = 4.8 Hz), 7.37(1H, d, J = 6.8 Hz), 7.44(1H, d, J = 9.0 Hz), 8.58(2H, d,J = 4.8 Hz), 8.01(1H, br). 11-16 4-chloro-2- F Cl amorphous (acetone-d₆-CDCl₃) 4.73(1H, s), 6.22(1H, s), pyrimidyl 6.95(1H, d, J = 5.6 Hz), 7.29(1H, d, J = 6.6 Hz), 7.43(1H, d, J = 8.9 Hz), 8.51(1H, d, J = 5.6 Hz). 11-17 4,6-dime- F Cl amorphous (DMSO-d₆-CDCl₃), 3.81(6H, s), 5.85(1H, s), 6.20(1H, thoxy-2- s), 7.45(1H, d, J = 6.8 Hz), 7.54(1H, d, J = 9.1 Hz). pyrimidyl 11-18 2-nitro- F Cl mp 6.24(1H,s), 6.93(1H, d, J = 8.4 Hz), 7.06(1H, d, J = 6.4 phenyl 177-179 Hz), 7.24(1H, t, J = 8.0 Hz), 7.44(1H, d, J = 8.9 Hz), 7.53(1H, ddd, J = 8.4, 8.0, 1.6 Hz), 7.99(1H, dd, J = 8.0, 1.6 Hz), 9.10(1H, br s). 11-19 3-methyl- F Cl mp 3.40(3H, s), 6.16(1H, s), 7.27˜7.36(2H, m), 7.45(1H, sulfonyl-2- 262-264 d), 8.34˜8.40(2H, m), 12.70(1H, br. s). pyridyl 11-20 3-i-propyl- F Cl mp 1.36(6H, d), 3.95(1H, q), 6.16(1H, s), 7.27˜7.35(3H, sulfonyl-2- 275-277 m) 7.45(1H, d), 8.35(1H, d), 12.7(1H, br.s). pyridyl 11-21 4-nitrophenyl F Cl amorphous 6.17(1H, s), 7.09(2H, d, J = 9.2 Hz), 7.24(1H, d, J = 6.5 Hz), 7.50(1H, d, J = 8.9 Hz), 8.23(2H, d, J = 9.2 Hz), 12.6(1H, br). 11-22 4-nitro-2- F Cl amorphous 6.28(1H, s), 6.86(1H, d, J = 9.1 Hz), 7.21(1H, d,J = 6.5 trifluorome- Hz), 7.50(1H, d, J = 8.7 Hz), 8.34(1H, dd, J = 9.1, 2.7 thylphenyl Hz), 8 61(1H, d, J = 2.5 Hz). 11-23 3-nitro-5- F Cl amorphous 6.28(1H, s), 7.16(1H, d, J = 6.4 Hz), 7.51(1H, d, J = 8.8 trifluorome- Hz), 7.54(1H, br s), 7.94(1H, t, J = 2.0 Hz), 8.23(1H, thylphenyl br s), 9.60(1H, br s). 11-24 4-amino-2- F Cl amorphous 6.21(1H, s), 6.75(3H, m), 6.97(1H, s), 7.40(1H, d, trifluoromo- J = 9.0 Hz). thylphenyl 11-25 4-amino- F Cl amorphous 5.95(2H, br), 6.14(1H, s), 6.60(2H, d, J = 8.6 Hz), phenyl 6.69(1H, d, J = 6.7 Hz), 6.71(2H, d, J = 8.6 Hz), 7.32(1H, d, J = 8.9 Hz). 11-26 3-amino-5- F Cl amorphous 6.19(1H, s), 6.69(1H, br s), 6.81(1H, br s), 6.92(1H, trifluorome- br s) 6.97(1H, d, J = 6.4 Hz), 7.30(1H, br s), 7.38(1H, thylphenyl d, J = 9.0 Hz). 11-27 2-amino F Cl amorphous 6.19(1H, s), 6.69(1H, ddd, J = 9.4, 8.7, 1.2 Hz), phenyl 6.80(3H, m), 6.98(1H, ddd, J = 9.4, 8.5, 1.4 Hz), 7.38(1H, d, J = 8.9 Hz). 11-28 2-trifluoro- F Cl amorphous 6.24(1H, s), 6.83(1H, d, J = 8.2 Hz), 7.01(1H, d, J = 6.5 methyl- Hz), 7.20(1H, t, J = 7.6 Hz), 7.43(1H, d, J = 8.9 Hz), phenyl 7.47(1H, m), 7.70(1H, d, J = 7.6 Hz), 9.10(1H, br s). 11-29 3-trifluoro F Cl amorphous 6.25(1H, s), 6.98(1H, d, J = 6.6 Hz), 7.11(1H, d, m), methyl- 7.27(1H, br s), 7.44(1H, d, J = 8.8 Hz), 7.38-7.48(2H, phenyl m), 10.2(1H, br s). 11-31 4-hydroxy- F Cl amorpbous phenyl 11-32 1,4-(1-ethoxy- F Cl amorphous 1.25(3H, dd, J = 1.5, 7.1 Hz), 1.60(3H, d, J = 6.8 Hz), 1-carbonyl- 4.12(2H, dq, J = 1.5, 7.1 Hz), 4.68(1H, q, J = 6.8 Hz), 1-ethoxy)- 6.20(1H, s), 6.73(1H, d, J = 6.6 Hz), 6.84(2H, d, J = 9.1 phenyl Hz), 6.95(2H, d, J = 9.1 Hz), 7.37(1H, d, J = 8.9 Hz). 11-33 1,2-cyano- F Cl mp 6.26(1H, s), 6.75(1H, d, J = 8.4 Hz), 7.14(1H, d, J = 6.5 phenyl 240-246 Hz), 7.20(1H, t, J = 7.4 Hz), 7.45(1H, d, J = 8.8 Hz), 7.45(1H, ddd, J = 8.4, 7.4, 1.7 Hz), 7.68(1H, dd, J = 7.4, 1.7 Hz), 9.98(1H, br s). 11-34 2-cyano-3- F Cl mp 6.26(1H, s), 6.52(1H, d, J = 8.8 Hz), 6.94(1H, t, J = 8.4 fluorophenyl 215-218 Hz), 7.20(1H, d, J = 6.6 Hz), 7.41-7.49(2H, m).

TABLE 12 ¹H NMR data Compd No. ¹H NMR (CDCl₃, TMS) 1-1 4.06(3H, brs), 7.22(1H, dd, J=4.9, 8.0 Hz), 7.37(1H, d, J=9.1 Hz), 7.48(1H, d, J=6.4 Hz), 8.32(1H, dd, J=1.7, 4.8 Hz), 8.42(1H, dd, J=1.7, 7.9 Hz). 1-2 4.05(3H, m), 7.13(1H, m), 7.36(1H, d, J=9.1 Hz), 7.45(1H, d, J=6.6 Hz), 8.02(1H, m), 8.26(1H, m). 1-3 4.06(3H, s), 7.16(1H, dd, J=5.0, 7.5 Hz), 7.36(1H, d, J=9.1 Hz), 7.48(1H, d, J=6.5 Hz), 8.06(1H, br dd, J=1.7, 7.5 Hz), 8.3(1H, br dd, J=1.7, 5.0 Hz). 1-4 4.06(3H, s), 7.14(1H, d, J=8.6 Hz), 7.37(1H, d, J=9.1 Hz), 7.42(1H, d, J=6.5 Hz), 7.98 (1H, dd, J=2.3, 8.6 Hz), 8.43(1H, br d, J=2.1 Hz). 1-5 4.05(3H, s), 6.63(1H, dd, J=2.6, 8.0 Hz), 6.84(1H, br d, J=7.8 Hz), 7.34(1H, d, J=9.2 Hz), 7.42(1H, d, J=6.6 Hz), 7.80(1H, dd, J=8.0, 16.0 Hz). 1-6 4.05(3H, s), 7.33(1H, d, J=9.1 Hz), 7.44(1H, d, J=6.4 Hz), 7.52(1H, br dd, J=7.7, 14.8 Hz). 1-7 4.06(3H, s), 7.08(1H, dd, J=4.8 Hz), 7.36(1H, d, J=9.1 Hz), 7.47(1H, d, J=6.6 Hz), 8.58(2H, d, J=4.8 Hz). 1-8 4.01(6H, s), 4.07(3H, m), 7.35(1H, d, J=9.1 Hz), 7.45(1H, d, J=6.6 Hz). 2-1 2.60(3H, br s), 7.18(1H, t, J=58.1 Hz), 7.20(1H, dd, J=4.8, 7.9 Hz), 7.32(1H, d, J=9.3 Hz), 7.57(1H, d, J=6.6 Hz), 8.30(1H, dd, J=1.8, 4.8 Hz), 8.41(1H, dd, J=1.8, 7.9 Hz). 2-2 2.60(3H, br s), 7.11(1H, m), 7.15(1H, t, J=58.1 Hz), 7.31(1H, d, J=9.5 Hz), 7.54(1H, d, J=6.7 Hz), 8.01(1H, m), 8.24(1H, m). 2-3 2.61(3H, br s), 7.07(1H, t, J=4.8 Hz), 7.17(1H, t, J=58.1 Hz), 7.32(1H, d, J=9.5 Hz), 7.56(1H, d, J=6.7 Hz), 8.56(2H, d, J=4.8 Hz). 2-4 2.61(3H, br s), 4.00(6H, s), 7.17(1H, t, J=58.1 Hz), 7.29(1H, d, J=9.3 Hz), 7.53(1H, d, J=6.6 Hz). 3-1 2.48(3H, br s), 7.05(1H, t, J=58.0 Hz), 7.09(1H, t, J=4.8 Hz), 7.37(1H, d, J=9.5 Hz), 7.48(1H, d, J=6.8 Hz), 8.57(2H, d, J=4.8 Hz). 4-1 1.90(3H, s), 2.30(3H, s), 7.12(1H, dd, J=5.7 Hz), 7.30(1H, d, J=7 Hz), 7.40(1H, d, J=9 Hz), 8.00(1H, d, J=7 Hz), 8.25(1H, m), 8.62(1H, s). 4-2 1.98(2H, m), 2.41(2H, m), 3.75(2H, m), 6.24(1H, t, J=4.5 Hz), 7.14(1H, m), 7.31(1H, d, J=6.7 Hz), 7.41(1H, d, J=9.1 Hz), 8.01(1H, m), 8.25(1H, m). 5-1 2.20(2H, m), 3.00(2H, m), 3.99(2H, m), 5.71(1H, s), 6.92(1H, m), 7.08(1H, d, J=6.6 Hz), 7.20(1H, m), 7.39(1H, d, J=8.8 Hz), 7.50(1H, m), 7.94(1H, m). 5-2 2.21(2H, m), 3.01(2H, t, J=8.1 Hz), 3.99(2H, m), 5.73(1H, s), 7.02(2H, d, J=9.3 Hz), 7.11(1H, d, J=6.6 Hz), 7.41(1H, d, J=8.9 Hz), 8.20(2H, d, J=9.3 Hz). 5-3 2.18(2H, m), 2.95(2H, t, J=7.7 Hz), 3.6(2H, br), 3.95(2H, m), 5.67(1H, s), 6.62(2H, d, J=8.9 Hz), 6.70(1H, d, J=6.7 Hz), 6.85(2H, d, J=8.9 Hz), 7.31(1H, d, J=8.9 Hz). 5-5 2.22(2H, m), 3.10(2H, m), 3.52(3H, s), 3.99(2H, m), 5.69(1H, s), 7.08(2H, d, J=9.1 Hz), 7.37(1H, d, J=6.8 Hz), 7.56(2H, d, J=9.1 Hz), 7.67(1H, d, J=9.3 Hz). 5-6 2.17(2H, m), 2.97(2H, m), 3.96(2H, m), 6.65(2H, d, J=8.9 Hz), 6.72(1H, d, J=6.7 Hz), 6.84(2H, d, J=9.0 Hz), 7.02(1H, s), 7.32(1H, d, J=8.9 Hz). 5-7 2.21(2H, m), 3.01(2H, t, J=7.8 Hz), 4.01(2H, m), 5.74(1H, s), 6.97(1H, m), 7.21(1H, d, J=6.7 Hz), 7.37(1H, d, J=9.0 Hz), 7.75(1H, m), 7.98(1H, m). 5-8 2.21(2H, m), 3.01(2H, t, J=7.8 Hz), 4.02(2H, m), 5.73(1H, s), 7.18(1H, m), 7.22(1H, d, J=6.8 Hz), 7.37(1H, d, J=8.9 Hz), 8.30(1H, m), 8.39(1H, m). 5-9 2.19(2H, m), 3.00(2H, m), 3.99(2H, m), 5.73(1H, s), 7.12(1H, m), 7.23(1H, d, J=6.6 Hz), 7.35(1H, d, J=8.9 Hz), 8.00(1H, m), 8.26(1H, m). 5-10 2.20(2H, m), 3.00(2H, t, J=8.0 Hz), 3.99(2H, m), 5.74(1H, s), 7.10(1H, m), 7.24(1H, m), 7.36(1H, d, J=8.9 Hz), 7.99(1H, d, J=6.6 Hz), 8.25(1H, m). 5-11 2.20(2H, m), 3.00(2H, t, J=7.9 Hz), 4.00(2H, m), 5.74(1H, s), 7.09(1H, d, J=8.6 Hz), 7.18(1H, d, J=6.7 Hz), 7.37(1H, d, J=8.9 Hz), 7.94(1H, m), 8.41(1H, d, J=2.3 Hz). 5-12 2.20(2H, m), 3.00(2H, t, J=7.8 Hz), 4.00(2H, m), 5.73(1H, s), 7.05(1H, t, J=4.8 Hz), 7.22(1H, d, J=6.8 Hz), 7.36(1H, d, J=9.0 Hz), 8.54(2H, d, J=4.7 Hz). 6-1 2.29(2H, dtt, J=26.4, 6.9, 5.6 Hz), 4.20(2H, t, J=6.9 Hz), 4.60(2H, dt, J=46.9, 5.6 Hz), 6.65(1H, d, J=8.3 Hz), 6.90-7.15(3H, m), 7.72(1H, m), 8.18(1H, m). 6-2 2.29(2H, dtt, J=26.4, 6.9, 5.6 Hz), 4.20(2H, t, J=6.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.27(1H, dd, J=8.0, 4.8 Hz), 7.49(1H, d, J=9.3 Hz), 7.61(1H, d, J=6.7 Hz), 8.31(1H, dd, J=4.8, 1.7 Hz), 8.45(1H, dd, J=8.0, 1.7 Hz). 6-6 2.28(2H, dtt, J=26.4, 7.0, 5.8 Hz), 4.19(2H, t, J=7.0 Hz), 4.58(2H, dt, J=46.7, 5.8 Hz), 7.16(1H, dd, J=7.5, 5.0 Hz), 7.47(1H, d, J=9.4 Hz), 7.58(1H, d, J=6.7 Hz), 8.03(1H, d, J=7.5 Hz), 8.24(1H, d, J=5.0 Hz). 6-7 2.29(2H, dtt, J=26.4, 5.9, 5.6 Hz), 4.20(2H, t, J=5.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.15(1H, m), 7.47(1H, s), 7.58(1H, s), 8.03(1H, m), 8.24(1H, m). 6-8 2.29(2H, dtt, J=26.4, 6.9, 5.6 Hz), 4.20(2H, t, J=6.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.16(1H, d, J=8.6 Hz), 7.47(1H, d, J=9.3 Hz), 7.54(1H, d, J=6.7 Hz), 7.97(1H, dd, J=8.6, 2.5 Hz), 8.38(1H, d, J=2.5 Hz). 6-9 2.30(2H, dtt, J=26.4, 6.9, 5.6 Hz), 4.20(2H, t, J=6.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.16(1H, dd, J=8.7, 0.7 Hz), 7.44(1H, s), 7.73(1H, s), 7.97(1H, dd, J=8.7, 2.5 Hz), 8.38(1H, dd, J=2.5, 0.7 Hz). 6-10 2.30(2H, m), 4.20(2H, t, J=6.9 Hz), 4.59(2H, dt, J=46.9, 6.6 Hz), 7.13(1H, dd, J=4.8 Hz), 7.48(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.8 Hz), 8.58(2H, d, J=4.8 Hz). 6-11 1.51(3H, t, J=7.3 Hz), 4.08(2H, q, J=7.3 Hz), 7.12(1H, dd, J=4.8 Hz), 7.47(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.7 Hz), 8.58(2H, d, J=4.8 Hz). 6-12 3.79(2H, t, J=5.4 Hz), 4.20(2H, t, J=5.4 Hz), 7.10(1H, dd, J=5.8 Hz), 7.45(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.8 Hz), 8.56(2H, d, J=5.8 Hz). 6-13 3.07(2H, t, J=6.7 Hz), 4.38(2H, t, J=6.7 Hz), 7.20(2H, m), 7.55(1H, d, J=9.3 Hz), 8.58(2H, d, J=5.8 Hz). 6-14 2.29(2H, dtt, J=26.5, 5.9, 5.6 Hz), 4.20(2H, t, J=5.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.14(1H, dd, J=4.8 Hz), 7.52(1H, s), 7.74(1H, s), 8.57(2H, d, J=4.8 Hz). 6-15 2.30(2H, dtt, J=26.4, 6.9, 5.5 Hz), 3.84(6H, s), 4.20(2H, t, J=6.9 Hz), 4.59(2H, dt, J=47.0, 5.5 Hz), 5.82(1H, s), 7.46(1H, d, J=9.3 Hz), 7.57(1H, d, J=6.8 Hz). 6-16 2.30(2H, dtt, J=26.3, 7.1, 5.5 Hz), 4.19(2H, t, J=7.1 Hz), 4.58(2H, dt, J=46.9, 5.5 Hz), 7.49(1H, d, J=9.3 Hz), 7.59(1H, d, J=6.6 Hz), 8.58(2H, s). 6-17 2.30(2H, dtt, J=26.4, 6.9, 5.6 Hz), 2.69(3H, s), 4.20(2H, t, J=6.9 Hz), 4.58(2H, dt, J=47.0, 5.6 Hz), 7.61(1H, s), 7.84(1H, s). 7-1 1.86(4H, m), 3.76(4H, m), 6.90(1H, d, J=7.6 Hz), 7.13(1H, m), 7.25(1H, d, J=9.7 Hz), 8.02(1H, m), 8.27(1H, m). 7-2 1.85(4H, m), 3.74(4H, m), 6.89(1H, d), 7.04(1H, t), 7.25(1H, d), 8.56(2H, d). 8-1 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m). 8-2 1.25(3H, t, J=7.3 Hz), 3.54(2H, q, J=7.3 Hz), 4.08(2H, s), 7.09(1H, t, J=4.8 Hz), 7.31(1H, d, J=6.7 Hz), 7.40(1H, d, J=9.2 Hz), 8.56(2H, d, J=4.8 Hz). 8-3 3.05(3H, s), 4.09(2H, s), 7.09(1H, t, J=4.8 Hz), 7.30(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.2 Hz), 8.54(2H, d, J=4.8 Hz). 8-4 1.47(3H, m), 1.78(1H, m), 2.03(1H, m), 2.27(1H, m), 2.91(1H, m), 3.96(1H, m), 4.22(1H, m), 7.11(1H, m), 7.28(1H, d, J=6.7 Hz), 7.37(1H, d, J=9.1 Hz), 8.00(1H, m), 8.22(1H, m). 8-5 1.94(4H, m), 3.68(2H, m), 3.98(2H, m), 7.05(3H, m), 7.12(1H, m), 7.35(2H, m), 7.41(1H, m). 8-6 1.93(4H, m), 3.69(2H, m), 3.96(2H, m), 6.98(1H, d, J=8.3 Hz), 7.21(2H, m), 7.43(1H, d, J=8.9 Hz), 7.50(1H, m), 7.95(1H, d, J=8.0 Hz). 8-7 1.96(4H, m), 3.70(2H, m), 4.00(2H, m), 6.83(1H, d, J=8.6 Hz), 7.16(1H, m), 7.29(1H, m), 7.48(2H, m), 7.67(1H, m). 8-8 1.97(4H, m), 3.68(2H, m), 3.98(2H, m), 7.07(2H, d, J=9.1 Hz), 7.30(1H, d, J=6.6 Hz), 7.47(1H, d, J=8.8 Hz), 8.24(2H, d, J=9.1 Hz). 8-9 1.94(4H, m), 3.66(2H, m), 3.68(2H, m), 3.98(2H, m), 6.66(2H, d, J=8.9 Hz), 6.86(1H, d, J=6.6 Hz), 6.90(2H, d, J=8.9 Hz), 7.38(1H, d, J=8.9 Hz). 8-11 1.26(3H, t, J=7.1 Hz), 1.60(3H, d, J=6.8 Hz), 1.94(4H, m), 3.68(2H, m), 3.98(2H, m), 4.22(2H, q, J=7.1 Hz), 4.68(1H, q, J=6.8 Hz), 6.85(2H, d, J=8.8 Hz), 6.89(1H, d, J=6.5 Hz), 6.98(2H, d, J=8.9 Hz), 7.37(1H, d, J=8.9 Hz). 8-12 1.99(4H, m), 3.71(2H, m), 4.02(2H, m), 6.95(1H, d, J=9.3 Hz), 7.42(1H, d, J=6.4 Hz), 7.51(1H, d, J=8.7 Hz), 8.37(1H, m), 8.59(1H, d, J=2.7 Hz). 8-14 1.98(4H, m), 3.70(2H, m), 4.02(2H, m), 6.95(1H, d, J=9.1 Hz), 7.36(1H, d, J=6.4 Hz), 7.50(1H, d, J=8.8 Hz), 8.35(1H, m), 8.60(1H, d, J=2.5 Hz). 8-15 1.97(4H, m), 3.74(2H, m), 3.79(2H, br), 4.02(2H, m), 6.46(1H, d), 6.72(1H, d), 7.13(1H, d), 7.64(1H, m), 7.73(1H, d). 8-16 1.92(4H, m), 2.10(3H, s), 3.67(2H, m), 3.96(2H, m), 6.85(1H, d, J=9.1 Hz), 7.05(1H, d, J=6.3 Hz), 7.38(1H, d, J=8.9 Hz), 7.62(1H, m), 7.82(1H, s), 8.26(1H, s). 8-17 1.90(4H, m), 3.66(2H, m), 3.97(2H, m), 6.97(2H, m), 7.33(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.0 Hz), 7.68(1H, m), 8.10(1H, m). 8-18 1.95(4H, m), 3.71(2H, m), 4.01(2H, m), 7.13(1H, m), 7.38(1H, d, J=6.7 Hz), 7.42(1H, d, J=9.0 Hz), 8.00(1H, m), 8.24(1H, m). 8-19 1.97(4H, m), 3.71(2H, m), 4.01(2H, m), 7.21(1H, m), 7.40(1H, d, J=6.6 Hz), 7.42(1H, d, J=8.8 Hz), 8.30(1H, m), 8.39(1H, m). 8-20 1.97(4H, m), 3.71(2H, m), 4.02(2H, m), 7.14(1H, m), 7.41(1H, d, J=6.6 Hz), 7.43(1H, d, J=8.9 Hz), 8.04(1H, m), 8.28(1H, m). 8-21 1.96(4H, m), 3.38(3H, s), 3.69(2H, m), 4.00(2H, m), 7.24(1H, m), 7.44(2H, m), 8.32(1H, m), 8.38(1H, m). 8-22 1.95(4H, m), 3.71(2H, m), 4.02(2H, m), 7.12(1H, d, J=8.6 Hz), 7.35(1H, d, J=6.6 Hz), 7.43(1H, d, J=8.9 Hz), 7.96(1H, m), 8.42(1H, d, J=2.4 Hz). 8-23 1.97(4H, m), 3.71(2H, m), 4.02(2H, m), 7.12(1H, d, J=9.0 Hz), 7.38(1H, d; J=6.7 Hz), 7.43(1H, d, J=9.0 Hz), 8.53(1H, m), 8.99(1H, m). 8-24 1.93(4H, m), 3.68(2H, m), 3.98(2H, m), 6.79(1H, d, J=8.7 Hz), 7.04(1H, m), 7.20(1H d, J=6.6 Hz), 7.34(1H, d, J=9.0 Hz), 7.59(1H, d, J=2.9 Hz). 8-25 1.92(4H, m), 3.67(2H, m), 3.98(2H, m), 6.61(1H, m), 6.80(1H, m), 7.35(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.0 Hz), 7.78(1H, m). 8-26 1.97(4H, m), 3.72(2H, m), 4.02(2H, m), 6.85(1H, m), 7.07(1H, m), 7.37(1H, d, J=6.6 Hz), 7.41(1H, d, J=8.9 Hz), 7.66(1H, m). 8-27 1.95(4H, m), 3.68(2H, m), 4.00(2H, m), 6.98(1H, d, J=8.5 Hz), 7.38(1H, d, J=6.6 Hz), 7.43(1H, d, J=8.9 Hz), 8.01(1H, d, J=8.5 Hz). 8-28 1.96(4H, m), 3.71(2H, m), 4.00(2H, m), 7.38(1H, d, J=6.9 Hz), 7.42(1H, d, J=8.8 Hz), 7.54(1H, m). 8-29 1.92(4H, m), 3.69(2H, m), 3.99(2H, m), 7.05(1H, m), 7.37(1H, d, J=6.5 Hz), 7.39(1H d, J=9.0 Hz), 8.53(2H, d, J=4.8 Hz). 8-30 1.96(4H, m), 3.71(2H, m), 4.00(2H, m), 7.41(3H, m), 8.77(1H, d, J=4.9 Hz). 8-31 1.94(4H, m), 3.68(2H, m), 3.98(2H, m), 6.90(1H, d, J=5.7 Hz), 7.37(1H, d, J=6.5 Hz) 7.42(1H, d, J=8.9 Hz), 8.46(1H, d, J=5.7 Hz). 8-32 1.94(4H, m), 3.69(2H, m), 3.80(3H, s), 3.93(3H, s), 3.97(2H, m), 5.88(1H, s), 7.31(1H, d, J=6.6 Hz), 7.38(1H, d, J=8.9 Hz). 8-33 1.95(4H, m), 3.69(2H, m), 3.81(6H, s), 4.00(2H, m), 5.77(1H, s), 7.32(1H, d, J=6.7 Hz), 7.39(1H, d, J=8.9 Hz). 8-34 1.94(4H, m), 3.67(2H, m), 3.93(2H, m), 3.95(6H, s), 7.33(1H, d, 6.6 Hz), 7.39(1H, d, 8.9 Hz). 8-35 1.97(4H, m), 2.68(3H, s), 3.69(2H, m), 4.01(2H, m), 7.49(1H, d, J=8.7 Hz), 7.56(1H, d, J=6.3 Hz). 8-36 1.98(4H, m), 3.71(2H, m), 4.02(2H, m), 7.47(1H, d, J=8.7 Hz), 7.57(1H, d, J=6.4 Hz), 8.06(1H, s). 8-37 1.34(6H, 2d, J=5.8, 5.2 Hz), 1.94(4H, m), 3.67(2H, m), 3.97(1H, m), 3.99(2H, m), 7.21(1H, m), 7.39(1H, m), 7.41(1H, 2d, J=1.1, 4.3Hz), 8.27(1H, m), 8.33(1H, m). 8-38 1.30(3H, t, J=7.1 Hz), 1.70(3H, d, J=6.7 Hz), 1.96(4H, m), 3.70(2H, m), 4.00(2H, m), 4.26(2H, q, J=7.2 Hz), 4.79(1H, q, J=6.9 Hz), 7.13(1H, d, J=10.4 Hz), 7.14(1H, m), 7.43(1H, d, J=8.8 Hz), 7.53(1H, s). 8-39 1.27(3H, t, J=7.1 Hz), 1.63(3H, d, J=6.8 Hz), 1.94(4H, m), 3.67(2H, m), 3.97(2H, m), 4.22(2H q, J=7.1 Hz), 4.74(1H, q, J=6.7 Hz), 7.00(1H, d, J=9.0 Hz), 7.02(1H, d, J=6.4 Hz), 7.10(1H, dd, J=3.0, 9.2 Hz), 7.41(1H, d, J=8.8 Hz), 7.46(1H, d, J=3.0 Hz). 8-40 1.27(3H t, J=7.1 Hz), 1.62(3H, d, J=6.8 Hz), 1.95(4H, m), 3.68(2H, m), 3.99(2H, m), 4.23(2H, q, J=7.2 Hz), 4.46(1H, q, J=6.8 Hz), 6.19(1H, dd, J=2.9, 8.8 Hz), 6.36(1H, d, J=2.9 Hz), 6.83(1H, d, J=8.6 Hz), 6.85(1H, d, J=5.9 Hz), 7.38(1H, d, J=8.8 Hz). 8-41 1.29(3H, t, J=7.1 Hz), 1.65(3H, d, J=6.8 Hz), 1.85(4H, m), 3.61(4H, m), 4.24(2H, q, J=7.1 Hz), 4.76(1H, q, J=6.7 Hz), 6.98(1H, d, J=6.6 Hz), 6.99(1H, d, J=2.4 Hz), 7.12(1H, 2d, J=3.1, 9.1 Hz), 7.43(1H, d, J=8.9 Hz), 7.48(1H, d, J=3.1 Hz). 8-42 1.94(4H, m), 3.69(2H, m), 4.01(2H, m), 5.52(2H, br), 6.85(1H, dd, J=4.9, 7.7 Hz), 7.03(1H, dd, J=1.6, 7.6 Hz), 7.39(1H, d, J=9.0 Hz), 7.43(1H, d, J=6.7 Hz), 7.48(1H, dd, J=1.6, 4.8 Hz). 8-43 1.95(4H, m), 2.50(3H, s), 3.69(2H, m), 3.98(2H, m), 7.02(1H, dd, J=6.9, 7.5 Hz), 7.38(1H, d, J=6.9 Hz), 7.41(1H, d, J=9.2 Hz), 7.53(1H, dd, J=1.5, 7.6 Hz), 7.84(1H, dd, J=1.6, 4.9 Hz). 8-47 1.63(3H, m), 1.89(1H, m, 2.10(1H, m), 2.37(1H, m), 2.12(1H, m), 4.11(1H, m), 4.89 (1H, d, J=13.5 Hz), 7.1(1H, t, J=4.8 Hz), 7.28-7.33(1H, 2xd) J=8.5, 7.0 Hz), 7.40(1H, d, J=8.9 Hz), 8.57(2H, d, J=4.9 Hz). 8-48 1.50(3H, m), 1.70(1H, m), 1.89(1H, m), 2.06(1H, m), 3.98(1H, m), 4.22(1H, m), 7.35 (1H, t, J=4.8 Hz), 7.64(1H, d, J=6.9 Hz), 7.90(1H, d, J=9.47 Hz), 8.70(2H, d, J=4.8 Hz). 8-49 1.63(3H, m), 1.89(1H, m), 2.10(1H, m), 2.37(1H, m), 2.12(1H, m), 4.11(1H, m), 4.89 (1H, d, J=13.5 Hz), 7.09(1H, t, J=4.8 Hz), 7.28-7.33(1H, 2×d, J=8.5, 7.0 Hz), 7.40(1H, d, J=8.9 Hz), 8.57(2H, d, J=4.9 Hz). 8-50 1.88(1H, m), 2.35(3H, m), 3.66(1H, m), 4.08(1H, m), 4.42(1H, m), 7.09(1H, t, J=4.8 Hz), 7.28-7.32(1H, 2×d, J=6.1, 6.7 Hz), 8.57(2H, d, J=4.8 Hz). 8-51 1.57(3H, m), 1.87(1H, m), 2.07(1H, m), 2.32(1H, m), 3.06(1H, m), 4.06(1H, m), 4.84 (1H, d, J=13.34 Hz), 7.18(7H, m). 8-52 1.61(3H, m), 1.90(1H, m), 2.06(1H, m), 2.33(1H, m), 3.08(1H, m), 4.08(1H, m), 4.85 (1H, d, J=13.5 Hz), 6.98(1H, m), 7.20(2H, m), 7.42(1H, d, J=8.8 Hz), 7.54(1H, m), 7.98(1H, dd, J=1.6, 8.1 Hz). 8-53 1.61(3H, m), 1.91(1H, m), 2.10(1H, m), 2.37(1H, m), 3.12(1H, m), 4.10(1H, m), 4.86 (1H, d, J=13.6 Hz), 6.82(1H, d, J=8.5 Hz), 7.21(2H, m), 7.48(2H, m), 7.68(1H, dd, J=1.6, 7.7 Hz). 8-54 1.63(3H, m), 1.90(1H, m), 2.07(1H, m), 2.34(1H, m), 3.09(1H, m), 4.07(1H, m), 4.88 (1H, d, J=13.5 Hz), 7.29(1H, m), 7.41(1H, d, J=4.8 Hz), 8.09(1H, dd, J=2.5, 3.9 Hz), 8.30(1H, d, J=2.7 Hz), 8.51(1H, d, J=1.1 Hz). 8-55 1.60(3H, m), 1.89(1H, m), 2.09(1H, m), 2.36(1H, m), 3.10(1H, m), 4.10(1H, m), 4.87 (1H, d, J=13.5 Hz), 7.01(2H, m), 7.26(1H, m), 7.38(1H, d, J=9.0 Hz), 7.71(1H, m), 8.15(1H, d, J=2.3 Hz). 8-56 1.59(3H, m), 1.9(1H, m), 2.08(1H, m), 2.35(1H, m), 3.10(1H, m), 4.08(1H, m), 5.90 (1H, d, J=14.0 Hz), 6.99(1H, m), 7.32(2H, m), 7.76(1H, dd, J=1.68, 7.7 Hz), 8.00(1H, d, J=2.9 Hz). 8-57 1.57(3H, m), 1.86(1H, m), 2.06(1H, m), 2.30(1H, m), 3.08(1H, m), 4.09(1H, m), 4.85 (1H, d, J=13.5 Hz), 7.32(2H, m), 7.99(1H, d, J=2.1 Hz), 8.25(1H, s). 8-58 1.61(3H, m), 1.87(1H, m), 2.09(1H, m), 2.34(1H, m), 3.12(1H, m), 4.10(1H, m), 4.88 (1H, d, J=13.5 Hz), 7.12(1H, m), 7.26(1H, m), 7.38(1H, d, J=8.9 Hz), 8.00(1H, dd, J=1.1, 6.4 Hz), 8.26(1H, d, J=2.4 Hz). 8-59 1.61(3H, m), 1.90(1H, m), 2.07(1H, m), 2.37(1H, m), 3.10(1H, m), 4.10(1H, m), 4.89(1H, d, J=13.5 Hz), 7.33(3H, m), 8.40(1H, d, J=1.4 Hz), 8.42(1H, d, J=1.30 Hz). 8-60 1.61(3H, m), 1.89(1H, m), 2.06(1H, m), 2.37(1H, m), 3.10(1H, m), 4.11(1H, m). 4.90 (1H, d, J=15.4 Hz), 7.16(1H, m), 7.36(2H, m), 8.03(1H, dd, J=2.0, 7.3 Hz), 8.31(1H, m). 8-61 1.60(3H, m), 1.87(1H, m), 2.07(1H, m), 2.35(1H, m), 3.10(1H, m), 4.00(2H, s), 4.11(1H, m), 4.87(1H, d, J=12.1 H), 6.85(1H, m), 7.02(1H, m), 7.49(3H, m). 8-62 1.56(3H, m), 1.87(1H, m), 2.05(1H, m), 2.30(1H, m), 3.05(1H, m), 3, 86(2H, d, J=4.51 Hz), 4.09(1H, m), 4.83(1H, d, J=13.2 Hz), 6.87(5H, m), 7.37(1H, d, J=8.8 Hz). 8-63 1.60(3H, m), 1.90(1H, m), 2.10(1H, m), 2.28(3H, s), 2.32(1H, m), 3.10(1H, m), 4.10(1H, m), 8.70(1H, d, J=14.0 Hz), 7.07(1H, m), 7.40(1H, m), 7.77(1H, m), 7.85(1H, s), 8.73(1H, dd, J=1.2, 7.9 Hz). 8-64 1.56(3H, m), 1.88(1H, m), 2.07(1H, m), 2.33(1H, m), 3.06(1H, m), 4.09(1H, m), 4.84 (1H, d, J=13.0 Hz), 6.90(1H, d, J=8.2 Hz), 7.26(9H, m), 7.89(2H, d, J=7.0 Hz), 8.10(2H, m), 8.60(2H, m). 9-1 4.62(2H, s), 6.27(1H, s), 7.21(1H, m), 7.25(1H, d, J=7.5 Hz), 7.42(1H, d, J=9.0 Hz), 8.32(1H, dd, J=4.8, 1.8 Hz), 8.41(1H, dd, J=7.9, 1.8 Hz). 9-2 4.63(2H, s), 6.26(1H, s), 6, 93(1H, d, J=8.7 Hz), 7.17(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.0 Hz), 7.80(1H, dd, J=8.7, 1.7 Hz), 8.14(1H, d, J=1.7 Hz). 9-3 4.62(2H, s), 6.26(1H, s), 6.97(1H, d, J=8.7 Hz), 7.17(1H, d, J=6.7 Hz), 7.40(1H, d, J=9.0 Hz), 7.67(1H, dd, J=8.7, 2.6 Hz), 8.42(1H, d, J=2.6 Hz). 9-4 4.63(2H, s), 6.25(1H, s), 6.63(1H, dd, J=1.9, 7.9 Hz), 6.83(1H, d, J=8 Hz), 7.21(1H, d, J=6.6 Hz), 7.40(1H, d, J=8.9 Hz), 7.79(1H, dd, J=7.7, 15.6 Hz). 9-5 4.62(2H, s), 6.27(1H, s), 6.87(1H, m), 7.06(1H, m), 7.22(1H, m), 7.41(1H, m), 7.66(1H, m). 9-6 4.65(2H, s), 6.26(1H, s), 7.23(1H, d, J=6.6 Hz), 7.41(1H, d, J=9.0 Hz), 7.55(1H, m). 9-7 4.64(2H, s), 6.23(1H, s), 7.12(1H, dd, J=7.5, 5.0 Hz), 7.22(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.0 Hz), 7.99(1H, dd, J=7.5, 1.0 Hz), 8.23(1H, dd, J=5.0, 1.0 Hz). 9-8 4.61(2H, s), 6.28(1H, s), 7.23(3H, m), 7.43(1H, d, J=9 Hz), 8.27(1H, m). 9-9 4.63(2H, s), 6.26(1H, s), 7.15(1H, dd, J=5.2, 7.1 Hz), 7.26(1H, d, J=6.4 Hz), 7.42(1H, d, J=8.9 Hz), 8.04(1H, d, J=7.1 Hz), 8.29(1H, d, J=3.8 Hz). 9-10 4.64(2H, s), 6.27(1H, s), 7.13(1H, d, J=8.6 Hz), 7.2(1H, d, J=6.6 Hz), 7.43(1H, d, J=9 Hz), 7.97(1H, dd, J=2.3, 8.6 Hz), 8.41(1H, m). 9-11 4.64(2H, s), 6.27(1H, s), 7.16(1H, d, J=9 Hz), 7.23(1H, d, J=6.6 Hz), 7.44(1H, d, J=8.8 Hz), 8.52(1H, dd, J=2.8, 9.1 Hz), 8.99(1H, d, J=2.2 Hz). 9-12 4.64(2H, s), 6.25(1H, s), 7.13(1H, m), 7.13(1H, dd, J=9.4, 9.3 Hz), 7.24(1H, dd, J=7.5 7.4 Hz), 7.99(1H, m), 8.24(1H, m). 9-13 1.34(3H, t), 3.56(2H, q), 4.61(2H, br.s), 6.27(1H, s), 7.22-7.27(2H, m), 7.43(1H, d), 8.31(1H, d), 8.36(1H, m). 9-14 2.67(3H, s), 4.99(2H, s), 6.24(1H, s), 7.53(1H, d, J=6.3 Hz), 7.56(1H, d, J=8.7 Hz). 9-15 4.66(2H, s), 6.23(1H, s), 6.98(2H, m), 7.18(1H, d, J=6.8 Hz), 7.38(1H, d, J=9.1 Hz), 7.70(1H, m), 8.07(1H, m). 9-16 5.36(2H, s), 6.31(1H, s), 7.33(1H, t, J=4.8 Hz), 7.55(1H, d, J=6.9 Hz), 7.69(1H, d, J=9.3 Hz), 8.68(2H, d, J=4.8 Hz). 9-17 5.04(2H, s), 6.23(1H, s), 7.03(1H, d, J=5.6 Hz), 7.34(1H, d, J=6.6 Hz), 7.48(1H, d, J=8.9 Hz), 8.55(1H, d, J=5.6 Hz). 9-18 3.82(6H, s), 4.66(2H, br s), 5.79(1H, s), 6.24(1H, s), 7.19(1H, d, J=6.7 Hz), 7.39(1H, d, J=9.0 Hz). 9-19 3.33(3H, s), 5.61(2H, br.s), 6.43(1H, s), 7.44˜7.48(1H, m), 7.69(1H, d,) 7.96(1H, d), 8.38(1H, d), 8.47(1H, d). 9-20 1.30(6H, d), 3.87(1H, m), 5.50(2H, br.s), 6.27(1H, s), 7.40(1H, d), 7.56(1H, d), 7.73(1H, d), 7.35(1H, d), 7.43(1H, d). 9-21 4.60(2H, s), 6.26(1H, s), 6.96(1H, d, J=7.5 Hz), 7.03(1H, d, J=5.8 Hz), 7.25(1H, t, J=7.9 Hz), 7.46(1H, d, J=8.8 Hz), 7.54(1H, ddd, J=7.9, 7.5, 1.4 Hz), 7.98(1H, d, J=7.9, 1.4 Hz). 9-22 4.61(2H, s), 6.28(1H, s), 6.87(1H, d, J=9.2 Hz), 7.20(1H, d, J=6.5 Hz), 7.51(1H, d, J=8.7 Hz), 8.35(1H, dd, J=9.2, 2.8 Hz), 8.61(1H, d, J=2.8 Hz). 9-23 4.60(2H, s), 6.28(1H, s). 7.15(1H, d, J=6.4 Hz), 7.51(1H, d, J=8.8 Hz), 7.57(1H, br s), 7.95(1H, t, J=2.2 Hz), 8.24(1H, br s). 9-24 4.58(2H, s), 6.25(1H, s), 6.85(1H, d, J=8.4 Hz), 6.99(1H, d, J=6.5 Hz), 7.19(1H, t, J=7.7 Hz), 7.44(1H, d, J=8.8 Hz), 7.47(1H, t, J=7.4 Hz), 7.70(1H, d, J=7.7 Hz). 9-25 4.60(2H, s), 6.26(1H, s), 6.96(1H, d, J=6.5 Hz), 7.13(1H, dd, J=8.1, 1.9 Hz), 7.30(1H, br s), 7.38(1H, d, J=7.7 Hz), 7.44(1H, d, J=8.9 Hz), 7.46(1H, t, J=8.0 Hz). 9-26 4.58(2H, s), 6.23(1H, s), 6.86(1H, d, J=6.7 Hz), 7.02(2H, ddd, J=8.7, 2.0, 1.1 Hz), 7.14(1H, tt, J=7.5, 1.1 Hz), 7.36(2H, ddt, J=8.7, 7.5, 2.0 Hz), 7.40(1H, d, J=8.9 Hz). 9-27 1.25(3H, t, J=7.14 Hz), 1.60(3H, d, J=6.81 Hz), 4.21(2H, q, J=7.14 Hz), 4.55(2H, s), 4.67(1H, q, J=6.09 Hz), 6.21(1H, s), 6.72(1H, d, J=6.51 Hz), 6.82(2H, d, J=6.75), 6.95(2H, d, J=6.54 Hz), 7.36(1H, d, J=8.94 Hz). 9-28 4.62(2H, s), 6.94(2H, m), 7.14(1H, m), 7.39(1H, m), 7.66(1H, m), 8.07(1H, m). 9-29 4.66(2H, s), 6.95(1H, s), 7.21(2H, m), 7.40(1H, m), 8.31(1H, m), 8.41(1H, m). 9-30 4.59(2H, s), 6.27(1H, s), 6.79(1H, d, J=8.5 Hz), 7.12(1H, d, J=6.5 Hz), 7.17(1H, dt, J=7.6, 0.9 Hz), 7.45(1H, d, J=8.8 Hz), 7.50(1H, ddd, J=8.5, 7.6, 1.6 Hz), 7.68(1H, dd, J=7.6, 1.6 Hz). 9-31 4.59(2H, s), 6.28(1H, s), 6.55(1H, d, J=8.5 Hz), 6.94(1H, t, J=8.5 Hz), 7.18(1H, d, J=6.6 Hz), 7.43-7.49(2H, m).

The compounds of the present invention exhibit excellent herbicidal effects when used as an active ingredient (ai) of a herbicide. The herbicide can sometimes be used for a wide range of applications, for example on crop lands such as paddy fields, upland farms, orchards and mulberry fields, and non-crop lands such as forests, farm roads, playgrounds, and factory sites. The application method may be suitably selected for soil treatment application and foliar application.

The compounds of the present invention are capable of controlling noxious weeds including grass (gramineae) such as barnyardgrass (Echinochloa crus-galli), large crabgrass (Digilaria sanguinalis), green foxtail (Setaria viridis), goosegrass (Eleusine indica L.), wild oat (Avena fatua L.), Johnsongrass (Sorghum halepense), quackgrass (Agropyron repens), alexandergrass (Brachiaria plantaginea), paragrass (Panicum purpurascen), sprangletop (Leptochloa chinensis) and red sprangletop (Leptochloa panicea); sedges (or Cyperaceae) such as rice flatsedge (Cyperus iria L.), purple nutsedge (Cyperus rotundus L.), Japanese bulrush (Scirpus Juncoides), flatsedge (Cyperus serotinus), small-flower umbrellaplant (Cyperus difformis), slender spikerush (Eleocharis acicularis), and water chestnut (Eleocharis kuroguwai); alismataceae such as Japanese ribbon wapato (Sagittaria pygmaea), arrow-head (Sagittaria trifolia) and narrowleaf waterplantain (Alisma canaliculatum); pontederiaceae such as monochoria (Monochoria vaginalis) and monochoria species (Monochoria korsakowii); scrophulariaceae such as false pimpernel (Lindernia pyxidaria) and abunome (Dopatriuni Junceum); lythraceae such as toothcup (Rotala indica) and red stem (Ammannia multiflora); and broadleaves such as redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), momingglory (Ipomoea hederacea), lambsquarters (Chenopodium album), prickly sida (Sida spinosa L.), common pursiane (Portulaca oleracea L.), slender amaranth (Amaranthus viridis L.), sicklepod (Cassia obtusifolia), black nightshade (Solanum nigrum L.), pale smartweed (Polygonum lapathifolium L.), common chickweed (Stellaria media L.), common cocklebur (Xanthium strumarium L.), flexuous bittercress (Cardamine flexuosa WITH.), henbit (Lamium amplexicaule L.) and threeseeded copperleaf (Acalypha australis L.). Accordingly, it is useful for controlling noxious weeds non-selectively or selectively in the cultivation of a crop plant such as corn (Zea mays L.), soybean (Glycine max Merr.), cotton (Gossypium spp.), wheat (Triticum spp.), rice (Oryza sativa L.), barley (Hordeum vulgare L.), oat (Avena sativa L.), sorgo (Sorghum bicolor Moench), rape (Brassica napus L.), sunflower (Helianthus annuus L.), sugar beet (Beta vulgaris L.), sugar cane (Saccharum officinarum L.), Japanese lawngrass (Zoysia Japonica stend), peanut (Arachis hypogaea L.) or flax (Linum usitatissimum L.).

For use as herbicides, the active ingredients of this invention are formulated into herbicidal compositions by mixing herbicidally active amounts with inert ingredients known to the art to facilitate either the suspension, dissolution or emulsification of the active ingredient for the desired use. The type of formulation prepared recognizes the facts that formulation, crop and use pattern all can influence the activity and utility of the active ingredient in a particular use. Thus for agricultural use the present herbicidal compounds may be formulated as water dispersible granules, granules for direct application to soils, water soluble concentrates, wettable powders, dusts, solutions, emulsifiable concentrates (EC), microemulsion, suspoemulsion, invert emulsion or other types of formulations, depending on the desired weed targets, crops and application methods.

These herbicidal formulations may be applied to the target area (where suppression of unwanted vegetation is the objective) as dusts, granules or water or solvent diluted sprays. These formulation may contain as little as 0.1% to as much as 97% active ingredient by weight.

Dusts are admixtures of the active ingredient with finely ground materials such as clays (some examples include kaolin and montmorillonite clays), talc, granite dust or other organic or inorganic solids which act as dispersants and carriers for the active ingredient; these finely ground materials have an average particle size of less than 50 microns. A typical dust formulation will contain 1% active ingredient and 99% carrier.

Wettable powders are composed of finely ground particles which disperse rapidly in water or other spray carriers. Typical carriers include kaolin clays, Fullers earth, silicas and other absorbent, wettable inorganic materials. Wettable powders can be prepared to contain from 1 to 90% active ingredient, depending on the desired use pattern and the absorbability of the carrier. Wettable powders typically contain wetting or dispersing agents to assist dispersion in water or other carriers.

Water dispersible granules are granulated solids that freely disperse when mixed in water. This formulation typically consists of the active ingredient (0.1% to 95% active ingredient), a wetting agent (1-15% by weight), a dispersing agent (1 to 15% by weight) and an inert carrier (1-95% by weight). Watcr dispersible granules can be formed by mixing the ingredients intimately then adding a small amount of water on a rotating disc (said mechanism is commercially available) and collecting the agglomerated granules. Alternatively, the mixture of ingredients may be mixed with an optimal amount of liquid (water or other liquid) and passed through an extruder (said mechanism is commercially available) equipped with passages which allow for the fornation of small extruded granules. Alternatively, the mixture of ingredients can be granulated using a high speed mixer (said mechanism is commercially available) by adding a small amount of liquid and mixing at high speeds to affect agglomeration. Alternatively, the mixture of ingredients can be dispersed in water and dried by spraying the dispersion through a heated nozzle in a process known as spray drying (spray drying equipment is commercially available). After granulation the moisture content of granules is adjusted to an optimal level (generally less than 5%) and the product is sized to the desired mesh size.

Granules are granulated solids that do not disperse readily in water, but instead maintain their physical structure when applied to the soil using a dry granule applicator. These granulated solids may be made of clay, vegetable material such as corn cob grits, agglomerated silicas or other agglomerated organic or inorganic materials or compounds such as calcium sulfate. The formulation typically consists of the active ingredient (1 to 20%) dispersed on or absorbed into the granule. The granule may be produced by intimately mixing the active ingredient with the granules with or without a sticking agent to facilitate adhesion of the active ingredient to the granule surface, or by dissolving the active ingredient in a solvent, spraying the dissolved active ingredient and solvent onto the granule then drying to remove the solvent. Granular formulations are useful where in-furrow or banded application is desired.

Emulsifiable concentrates (EC) are homogeneous liquids composed of a solvent or mixture of solvents such as xylenes, heavy aromatic naphthas, isophorone or other proprietary commercial compositions derived from petroleum distillates, the active ingredient and an emulsifying agent or agents. For herbicidal use, the EC is added to water (or other spray carrier) and applied as a spray to the target area. The composition of an EC formulation can contain 0.1% to 95% active ingredient, 5 to 95% solvent or solvent mixture and 1 to 20% emulsifying agent or mixture of emulsifying agents.

Suspension concentrate (also known as flowable) formulations are liquid formulations consisting of a finely ground suspension of the active ingredient in a carrier, typically water or a non-aqueous carrier such as an oil. Suspension concentrates typically contain the active ingredient (5 to 50% by weight), carrier, wetting agent, dispersing agent, anti-freeze, viscosity modifiers and pH modifiers. For application, suspension concentrates are typically diluted with water and sprayed on the target area.

Solution concentrates are solutions of the active ingredient (1 to 70%) in solvents which have sufficient solvency to dissolve the desired amount of active ingredient. Because they are simple solutions without other inert ingredients such as wetting agents, additional additives are usually added to the spray tank mix before spraying to facilitate proper application.

Microemulsions are solutions consisting of the active ingredient (1 to 30%) dissolved in a surfactant or emulsifier, without any additional solvents. There are no additional solvents added to this formulation. Microemulsions are particularly useful when a low odor formulation is required such as in residential turfgrass applications.

Suspoemulsions are combinations of two active ingredients. One active ingredient is made as a suspension concentrate (1-50% active ingredient) and the second active is made as a emulsifiable concentrate (0.1 to 20%). A reason for making this kind of formulation is the inability to make an EC formulation of the first ingredient due to poor solubility in organic solvents. The suspoemulsion formulation allows for the combination of the two active ingredients to be packaged in one container, thereby minimizing packaging waste and giving greater convenience to the product user.

The herbicidal compounds of this invention may be formulated or applied with insecticides, fungicides, acaricides, nematicides, fertilizers, plant growth regulators or other agricultural chemicals. Certain tank mix additives, such as spreader stickers, penetration aids, wetting agents, surfactants, emulsifiers, humectants and UV protectants may be added in amounts of 0.01% to 5% to enhance the biological activity, stability, wetting, spreading on foliage or uptake of the active ingredients on the target area or to improve the suspensibility, dispersion, redispersion, emulsifiability, UV stability or other physical or physico-chemical property of the active ingredient in the spray tank, spray system or target area.

Now, Formulation Examples of the present invention will be given as follows.

Formulation example 1. Emulsifiable Concentrate Ingredient Chemical Trade Name Name Supplier Function % wt./wt. Compound 6-10 Active Ingredient 5.0 Toximul H-A Calcium sulfonate Stepan Co. Emulsifier 2.5 and nonionic surfactant blend Toximul D-A Calcium sulfonate Stepan Co. Emulsifier 7.5 and nonionic surfactant blend Aromatic 200 Aromatic Exxon Chemical Solvent QS to 100% hydrocarbon Co.

Formulation example 2. Suspension Concentrate Ingredient Chemical Trade Name Name Supplier Function % wt./wt. Compound 8-29 Active Ingredient 10.00 Proylene gylcol Anti-freeze 5.00 Antifoam 1530 Silicone defoamer Dow Corning Anti-foam 0.50 Rhodopol 23 Xanthan gum Rhone-Poulenc Suspending Aid 0.25 Morwet D-425 Napthalene Witco Corp. Dispersant 3.00 formaldehyde condensate Igepal CA-720 Octylphenol Rhone-Poulenc Wetting agent 3.00 ethoxylate Proxel GXL 1,2 benziso- ICI Americas Preservative 0.25 thiazolin-3-one Water Diluent 68.00

Formulation example 3. Wettable Powder Ingredient Chemical Trade Name Name Supplier Function % wt./wt. Compound 8-29 Active Ingredient 50.00 Geropon T-77 Sodium-N-methyl- Rhone-Poulenc Wetting agent 3.00 N-oleoyl taurate Lomar PW Naphthalene Henkel Corp. Dispersant 5.00 Sulfonate Kaolin clay Kaolin clay J. M. Huber Filler 42.00

Formulation example 4. Water Dispersible Granule Ingredient Chemical Trade Name Name Supplier Function % wt./wt. Compound 6-10 Active Ingredient 50.00 Morwet EFW Witco Corp. Wetting agent 2.00 Morwet D-425 Naphthalene Witco Corp. Dispersant 10.00 formaldehyde condensate ASP 400 Kaolin Clay Engelhard Filler 38.00 Corp.

Test Example

A standard greenhouse herbicide activity screening system was used to evaluate the herbicidal efficacy and crop safety of these test compounds. Six broadleaf weed species including redroot pigweed (Amaranthus retroflexus, AMARE), velvetleaf (Abutilon theophrasti, ABUTH), sicklepod (Cassia obtusifolia, CASOB), ivyleaf morningglory (Ipomoea hederacea, IPOHE), lambsquarters (Chenopodium album, CHEAL) and common ragweed (Ambrosia artemisiifolia L., AMBEL) were used as test species. Four grass weed species including green foxtail (Setaria viridis, SETVI), barnyardgrass (Echinociloa crusgalli, ECHCG), Johnsongrass (Sorghum halepense, SORHA), and large crabgrass (Digitaria sanguinalis, DIGSA) were also used. In addition, three crop species, field corn (Zea mays L., var. Dekalb 535, CORN), soybean (Glycine max L., var. Pella 86, SOY), and upland rice (Oryza sp., var.Tebonnet, RICE) were included.

Test Example 1. Pre-emerge test

All plants were grown in 10 cm square plastic pots which were filled with a sandy loam soil mix. For pre-emerge tests, seeds were planted one day prior to application of the test compounds. Immediately after application, test units of the pre-emerge applications were watered at the soil surface to incorporate the test materials. Subsequently, these test units were bottom-watered.

All test compounds were dissolved in acetone and applied to the test units in a volume of 187 l/ha. Test materials were applied at rates ranging from 125 g ai/ha to 1000 g ai/ha using a track sprayer equipped with a TJ8001E even flow flat fan spray nozzle. Plants were arranged on a shelf so that the top of the canopy (post-emerge) or top of the soil surface (pre-emerge) was 40-45 cm below the nozzle. Pressurized air was used to force the test solution through the nozzle as it was mechanically advanced (via electrically driven chain drive) over the top of all test plants/pots. This application simulates a typical commercial field herbicide application.

Test Example 2. Post-emerge test

In the post-emerge test, a commercial non-ionic surfactant was also included (0.25% v/v) to enhance wetting of the leaf surfaces of target plants at rates ranging from 63 g ai/ha to 1000 g ai/ha. For post-emerge tests, seeds were planted 8-21 days prior to the test to allow emergence and good foliage development prior to application of the test substances. At the time of the post-emerge application, plants of all species were usually at the 2-3 leaf stage of development. Post-emerge test units were always bottom-watered.

At 14 days after application of the test materials, phytotoxicity ratings were recorded. A rating scale of 0-100 was used as previously described in Research Methods in Weed Science, 2nd edition, B. Truelove, Ed., Southern Weed Science Society, Auburn University, Auburn, 1977. Briefly, “0” corresponds to no damage and “100” corresponds to complete death of all plants in the test unit. This scale was used both to determine efficacy against weed species and damage to crop species. Herbicide activity data for various compounds of this invention, which are shown by compound number in Tables 1-9, are shown in Tables 13 and 14. The data demonstrate significant differences between compounds for both efficacy against weeds and selectivity for crop species. For selected compounds, excellent activity against a majority of the weed species was observed with minimal damage to at least one of the crop species.

TABLE 13 Pre-emerge Herbicide Activity Compound Rate No. g ai/ha AMARE ABUTH CASOB IPOHE CHEAL AMBEL SETVI ECHCG SORHA DIGSA SOY CORN RICE 1-1  125 — — — — — — — — — — — — — 500 100 60 20 10 100 50 100 50 70 90 10 20 20 1-2  125 80 0 80 0 50 80 90 20 30 40 0 10 30 500 100 70 0 60 99 80 99 50 50 95 10 90 40 1-3  125 100 20 0 0 90 50 95 0 0 20 0 0 0 500 100 0 80 30 100 50 — 100 40 0 95 40 30 1-4  125 100 0 0 0 90 0 90 0 20 50 10 10 30 500 100 80 0 30 95 20 99 0 20 95 50 0 0 1-5  125 100 70 50 30 100 50 100 50 50 100 0 20 30 500 100 90 100 70 100 90 100 90 95 90 0 30 20 1-6  125 95 50 0 30 40 100 60 30 0 20 0 0 0 500 99 80 0 50 99 100 99 30 70 90 10 0 0 1-7  125 100 90 95 40 100 100 100 100 100 100 0 40 70 500 100 99 90 70 100 100 100 100 100 100 0 70 90 1-8  125 70 0 0 0 0 0 50 0 0 20 0 0 0 500 100 20 0 0 100 10 100 0 35 90 0 0 10 2-1  125 100 0 0 10 60 0 90 0 0 0 0 0 0 500 100 30 30 10 100 50 99 20 30 70 70 0 0 2-2  125 — — — — — — — — — — — — — 500 100 10 0 60 60 20 100 0 30 20 15 0 0 2-3  125 100 100 30 20 100 35 95 80 100 100 50 25 30 500 100 100 100 100 100 90 100 100 100 100 25 35 55 2-4  125 70 10 0 10 70 10 20 0 0 0 0 0 0 500 100 70 10 0 100 0 95 0 40 50 20 0 0 3-1  125 100 100 100 100 100 100 100 100 100 100 90 90 99 500 100 100 100 100 100 100 100 100 100 100 100 100 100 4-2  125 — — — — — — — — — — — — — 500 100 95 0 0 100 100 40 0 0 0 0 0 0 5-1  125 — — — — — — — — — — — — — 1000 99 100 40 70 100 — 99 95 90 100 55 5 70 5-2  125 — — — — — — — — — — — — — 1000 40 100 0 50 100 — 90 50 80 70 10 0 50 5-3  125 — — — — — — — — — — — — — 1000 100 99 10 0 0 — 20 0 40 70 40 0 20 5-5  125 — — — — — — — — — — — — — 500 95 50 0 0 100 — 0 0 0 0 10 0 0 5-6  125 — — — — — — — — — — — — — 1000 100 100 40 100 100 — 100 70 50 70 60 40 80 5-8  125 — — — — — — — — — — — — — 1000 100 100 0 80 100 — 95 85 95 100 50 15 50 5-9  125 — — — — — — — — — — — — — 1000 80 100 30 100 100 — 90 0 90 90 50 0 50 5-10 125 — — — — — — — — — — — — — 1000 100 100 0 100 100 — 100 100 100 100 80 70 80 5-11 125 — — — — — — — — — — — — — 1000 80 100 30 80 100 — 95 95 99 90 60 30 80 5-12 125 100 100 50 80 100 — 100 20 40 100 40 10 60 500 100 100 100 100 100 — 100 100 100 100 80 40 100 6-2  125 95 90 20 10 100 30 30 0 0 0 10 0 20 500 99 100 0 40 100 40 70 10 0 60 15 0 10 6-3  125 0 40 30 0 0 100 99 60 30 10 0 30 20 500 90 30 40 20 90 40 70 0 0 50 0 10 20 6-4  125 100 100 50 40 100 0 100 0 20 70 0 0 15 500 100 100 30 100 100 40 100 95 100 100 20 10 35 6-5  125 90 0 70 40 90 0 95 0 30 30 10 20 20 500 100 90 50 40 100 50 100 0 70 70 0 20 10 6-6  125 95 80 10 30 100 30 95 20 30 20 0 0 0 500 100 100 0 50 100 60 100 60 95 100 10 0 30 6-7  125 80 0 0 0 80 30 80 0 20 40 80 0 0 500 100 20 60 30 90 0 100 50 40 70 90 30 40 6-8  125 — — — — — — — — — — — — — 500 85 80 0 0 100 0 100 0 80 75 0 0 10 6-9  125 0 0 0 0 0 0 0 0 0 0 0 0 0 500 0 0 0 0 0 0 0 0 0 0 0 0 0 6-10 125 100 100 40 100 100 100 100 100 100 100 0 70 80 500 100 100 100 100 100 100 100 100 100 100 20 90 100 6-14 125 100 100 60 60 100 20 100 60 80 90 10 20 30 500 100 100 90 95 100 95 100 99 100 100 80 40 80 6-15 125 30 20 0 0 20 0 10 0 0 10 0 0 0 500 100 100 30 10 100 0 90 0 10 60 0 10 10 6-16 125 100 100 50 50 100 0 80 0 40 80 0 0 0 500 100 100 30 30 100 70 100 90 80 100 10 15 50 6-17 125 0 0 0 0 0 0 0 0 0 0 0 0 0 500 0 0 0 0 0 0 0 0 0 0 0 0 0 7-1  125 100 90 50 0 100 80 90 0 0 60 10 0 0 500 100 100 10 0 100 90 100 0 60 90 20 10 20 7-2  125 100 100 60 100 100 100 100 99 95 100 0 45 90 500 100 100 100 100 100 100 100 100 100 100 80 70 100 8-1  125 — — — — — — — — — — — — — 500 100 95 70 30 100 — 85 40 60 100 0 0 30 8-2  125 100 100 0 100 100 95 95 10 20 90 0 0 40 500 100 100 80 90 100 100 100 100 100 100 20 50 90 8-3  125 10 20 0 10 80 20 0 0 0 0 0 0 0 500 100 70 0 60 100 60 70 10 40 90 10 5 30 8-4  125 100 100 30 0 70 20 50 10 20 30 0 0 0 500 100 100 90 0 100 0 100 30 70 90 0 0 30 8-5  125 95 100 30 0 100 40 80 0 20 40 0 0 0 500 100 100 95 70 100 100 100 60 30 85 40 5 25 8-6  125 100 100 100 50 100 40 95 20 20 40 20 0 10 500 100 100 95 90 100 100 100 50 50 100 40 0 40 8-7  125 90 100 70 30 100 70 70 100 20 60 0 0 20 500 100 100 100 100 100 100 90 100 70 99 20 10 50 8-8  125 100 90 0 0 0 0 60 0 30 40 0 5 0 500 100 100 80 10 10 20 95 20 30 40 20 0 0 8-9  125 100 60 0 0 70 30 0 0 0 0 0 0 0 500 95 100 40 10 100 30 30 0 0 0 0 0 0 8-11 125 100 100 70 70 100 95 90 60 70 20 20 0 50 500 100 100 60 100 100 100 100 70 40 80 30 0 80 8-12 125 90 95 0 0 100 90 0 0 0 0 0 0 20 500 100 100 0 70 100 90 70 0 40 50 0 0 50 8-14 125 70 30 0 0 80 0 0 0 0 0 0 0 0 500 95 60 0 0 100 30 50 0 0 20 0 0 0 8-15 125 0 0 0 0 0 0 0 0 0 0 0 0 0 500 40 50 0 0 100 0 0 0 0 0 0 0 0 8-16 125 80 90 0 0 100 40 0 0 0 0 0 0 0 500 90 100 0 0 100 100 70 0 10 30 10 0 0 8-17 125 100 100 100 80 100 100 100 85 50 100 0 10 50 500 100 100 80 99 100 100 100 100 100 100 95 30 95 8-18 125 100 100 20 20 100 100 95 40 40 50 15 0 35 500 100 100 40 45 100 95 100 80 100 100 30 60 80 8-19 125 100 100 20 40 100 50 100 50 80 50 20 15 50 500 100 100 100 90 100 100 100 95 95 100 40 30 80 8-20 125 100 100 90 95 100 90 95 60 40 40 20 5 20 500 t00 100 100 100 100 100 100 80 90 100 25 10 40 8-21 125 100 100 70 90 100 70 99 40 80 70 0 0 40 500 100 100 100 100 100 90 100 90 100 100 80 10 95 8-22 125 100 100 20 40 100 100 40 0 0 20 50 0 0 500 100 100 90 10 100 100 100 30 20 90 70 60 40 8-23 125 90 95 0 30 100 0 10 0 0 0 0 0 0 500 100 100 50 60 100 60 100 10 30 50 20 0 0 8-24 125 95 100 70 0 99 80 30 0 20 0 0 0 0 500 100 100 50 70 100 100 80 40 20 30 30 0 20 8-25 125 100 100 70 20 100 40 100 40 70 85 0 0 15 500 100 100 100 20 100 90 100 100 90 100 20 40 70 8-26 125 — — — — — — — — — — — — — 500 0 0 0 0 0 0 0 0 0 0 0 0 0 8-27 125 100 50 0 0 80 0 60 0 0 10 0 0 0 500 100 100 80 30 100 0 100 0 30 50 0 0 10 8-28 125 100 100 100 30 100 80 100 60 90 100 10 15 25 500 100 100 90 40 100 100 100 95 95 100 10 15 70 8-29 125 100 100 100 100 100 100 100 100 100 100 90 80 90 500 100 100 100 100 100 100 100 100 100 100 100 95 100 8-30 125 100 100 100 100 100 100 100 40 40 70 80 10 20 500 100 100 100 90 100 99 100 99 99 100 80 20 90 8-31 125 100 100 30 0 90 30 0 0 0 0 40 0 0 500 100 100 90 70 100 0 90 20 20 70 0 0 10 8-32 125 50 95 30 40 90 0 10 0 10 20 0 0 0 500 100 100 80 90 100 50 100 20 30 90 0 10 40 8-33 125 100 100 40 0 100 0 80 0 0 10 0 0 10 500 100 100 90 70 100 40 100 20 40 90 30 0 10 8-34 125 100 100 0 0 100 40 80 0 20 10 10 0 20 500 100 100 40 80 100 100 99 40 80 80 0 5 50 8-35 125 100 100 30 50 100 50 90 10 20 10 0 0 30 500 100 100 100 100 100 90 100 90 90 80 30 30 70 8-36 125 100 100 90 90 100 90 80 0 20 70 0 0 30 250 100 100 70 70 100 100 99 70 50 80 100 20 70 8-37 125 100 100 0 30 100 100 100 30 20 80 50 0 500 100 100 80 85 100 100 100 100 80 100 80 25 80 8-38 125 30 100 0 0 80 0 0 0 0 0 0 0 250 80 100 0 30 90 0 70 0 0 0 0 0 0 8-39 125 100 20 95 0 99 — 0 0 0 0 0 0 0 250 100 100 0 0 100 — 40 0 0 0 0 0 20 8-40 125 60 50 0 0 50 — 0 0 0 0 0 0 0 250 100 30 20 0 100 — 0 0 0 0 0 0 0 8-41 125 80 0 0 0 70 — 10 0 0 0 0 0 0 250 100 70 0 0 90 — 50 0 0 0 0 0 0 8-42 125 100 100 100 30 80 0 0 0 0 0 0 0 0 250 100 100 80 50 100 30 0 0 0 0 20 0 0 8-43 125 20 10 20 0 100 — 100 0 0 90 0 0 20 250 70 30 30 20 100 — 100 0 0 100 0 0 20 9-1  125 100 100 30 100 100 99 95 95 95 40 5 40 500 100 100 90 100 100 100 100 99 100 80 60 90 9-2  125 80 30 0 0 100 80 20 60 95 0 0 10 500 100 100 50 100 100 100 95 90 100 80 70 60 9-3  125 100 100 0 40 100 100 30 70 95 0 10 20 500 100 100 70 100 100 100 99 99 100 50 70 80 9-4  125 100 100 60 100 100 100 100 99 100 80 60 40 500 100 100 100 100 100 100 100 100 100 95 95 99 9-5  125 100 100 10 70 100 100 90 95 95 40 15 50 500 100 100 80 80 100 100 100 100 100 40 70 90 9-6  125 100 100 90 90 100 100 90 90 100 20 50 50 500 100 100 100 95 100 100 100 90 100 75 70 85 9-7  125 100 100 40 70 100 100 90 90 100 50 30 60 500 100 100 100 100 100 100 100 100 100 90 99 80 9-8  125 100 100 80 95 100 40 30 50 20 60 50 50 500 100 100 90 100 100 100 99 99 100 50 70 80 9-9  125 100 100 100 100 100 100 100 100 100 100 90 90 500 100 100 100 100 100 100 100 100 100 100 99 99 9-10 125 100 100 100 100 100 100 90 95 90 100 80 50 500 100 100 100 100 100 100 100 100 100 100 90 90 9-11 125 100 100 10 10 100 70 10 20 30 0 5 10 500 100 100 20 100 100 100 80 90 95 50 10 60 9-14 125 100 100 100 100 100 100 95 95 100 80 80 65 500 100 100 90 100 100 100 90 100 100 15 40 50 9-15 125 100 100 95 100 100 100 100 100 100 80 70 80 500 100 100 100 100 100 100 100 100 100 95 90 100 9-16 125 100 100 100 100 100 100 100 100 100 100 100 100 500 100 100 100 100 100 100 100 100 100 100 100 100 9-17 125 100 100 20 20 100 90 20 30 30 0 0 10 500 100 100 70 100 100 100 100 90 100 90 50 70 9-21 125 100 100 30 60 100 100 90 90 100 30 25 80 500 100 100 90 100 100 100 100 100 100 90 60 90 9-22 125 100 100 30 90 100 90 50 50 80 10 5 15 500 100 100 80 80 100 100 90 95 100 70 30 75 9-23 125 100 40 0 0 95 40 10 10 10 10 10 10 500 100 100 10 0 100 100 70 70 95 15 5 60 9-24 125 95 99 30 30 100 100 60 30 90 30 10 15 500 100 100 0 30 100 100 70 90 100 60 30 80 9-25 125 100 100 30 70 100 100 70 80 80 50 20 40 500 100 100 80 90 100 100 95 100 100 80 40 90 9-26 125 100 100 95 100 100 100 95 90 100 70 15 70 500 100 100 100 60 100 100 100 100 100 70 75 90 9-28 125 100 100 50 40 100 100 20 20 70 20 0 10 500 100 100 50 70 100 100 80 80 100 50 60 50

TABLE 14 Post-emerge Herbicide Activity Compound Rate No. g ai/ha AMARE ABUTH CASOB IPOHE CHEAL AMBEL SETVI ECHCG SORHA DIGSA SOY CORN RICE 1-1  63 — — — — — — — — — — — — — 500 100 100 — 100 100 100 100 100 90 95 100 60 90 1-2  63 80 30 — 30 70 30 0 0 20 0 10 0 0 500 100 100 — 90 100 90 40 80 40 50 50 10 0 1-3  63 100 70 — 90 95 0 0 0 20 0 30 0 20 500 100 100 — 10 100 80 90 70 80 80 90 10 70 1-4  63 100 30 — 70 0 20 0 0 40 20 0 0 20 500 100 90 — 100 100 70 70 50 80 40 80 0 50 1-5  63 100 30 — 95 95 30 0 30 30 50 40 10 40 500 100 100 — 100 100 90 100 100 95 99 90 30 80 1-6  63 99 50 — 50 30 0 20 20 30 0 30 10 — 500 100 100 — 100 100 90 60 70 70 — 50 10 — 1-7  63 100 100 — 100 100 95 100 100 90 90 100 90 100 500 100 100 100 100 100 100 100 100 100 100 100 70 80 1-8  63 20 0 0 10 0 0 50 0 0 0 0 0 0 500 100 35 10 80 95 10 20 0 10 20 20 20 0 2-1  63 90 40 0 60 80 10 30 0 0 0 50 15 0 500 100 85 30 65 99 40 65 30 10 20 75 20 20 2-2  63 — — — — — — — — — — — — — 500 95 70 0 75 90 25 30 30 40 10 35 20 40 2-3  63 100 95 30 100 90 30 100 30 80 0 90 30 40 500 100 100 70 100 100 60 100 95 95 80 90 80 90 2-4  63 0 0 0 0 0 0 0 0 0 0 0 0 0 500 90 80 0 75 70 0 50 0 50 10 25 20 10 3-1  63 95 100 90 100 95 70 95 70 80 80 100 25 70 500 100 100 100 100 100 100 100 100 100 100 100 100 100 4-2  63 — — — — — — — — — — — — — 500 100 70 20 99 90 75 10 0 0 0 30 5 10 5-1  63 — — — — — — — — — — — — — 1000 30 100 10 90 80 — 20 30 10 0 40 0 10 5-2  63 — — — — — — — — — — — — — 1000 20 70 0 40 40 — 10 0 0 0 15 0 10 5-3  63 — — — — — — — — — — — — — 1000 0 0 0 0 0 — 0 0 0 0 0 0 0 5-5  63 — — — — — — — — — — — — — 500 0 0 0 0 0 — 0 0 0 0 0 0 0 5-6  63 — — — — — — — — — — — — — 1000 90 100 40 100 100 — 50 95 95 40 80 80 60 5-8  63 — — — — — — — — — — — — — 1000 40 100 30 80 60 — 10 0 0 0 20 0 0 5-9  63 — — — — — — — — — — — — — 1000 50 100 30 90 70 — 10 0 0 0 30 5 25 5-10 63 — — — — — — — — — — — — — 1000 80 100 30 70 80 — 20 80 70 10 15 30 30 5-11 63 — — — — — — — — — — — — — 1000 70 100 10 90 90 — 10 20 20 0 40 15 25 5-12 63 30 60 10 40 60 — 0 0 0 0 50 0 0 500 80 95 50 30 75 — 50 40 20 40 100 20 70 6-2  63 40 98 0 20 50 10 10 0 0 0 20 5 0 500 95 100 10 90 90 30 10 30 20 0 30 5 30 6-3  63 20 0 — 20 0 0 0 0 0 0 0 0 0 500 80 20 — 70 80 0 30 20 30 0 30 0 40 6-4  63 75 90 15 65 85 20 20 0 0 0 20 10 20 500 99 100 50 85 100 20 40 60 80 0 60 20 35 6-5  63 40 0 — 0 20 0 0 0 0 0 20 0 20 500 80 20 — 0 80 0 30 0 20 10 30 0 30 6-6  63 70 50 0 60 90 20 10 20 0 0 10 5 20 500 95 95 30 95 100 20 40 70 70 10 50 15 40 6-7  63 70 0 — 0 50 0 20 0 0 0 0 0 0 500 80 70 — 50 80 30 30 50 30 10 30 10 50 6-8  63 — — — — — — — — — — — — — 500 80 98 40 60 95 20 90 10 10 20 60 5 35 6-9  63 0 0 0 0 0 0 0 0 0 0 0 0 0 250 0 0 0 0 0 0 0 0 0 0 0 0 0 6-10 63 90 100 30 100 90 30 30 30 0 50 70 10 10 500 100 100 100 100 100 100 100 100 100 100 100 80 90 6-14 63 20 70 — 50 70 0 0 0 30 0 50 0 20 500 100 100 — 100 95 50 70 60 90 30 90 20 50 6-15 63 20 60 20 20 50 0 0 0 0 0 0 0 0 500 95 99 40 70 90 20 40 0 10 0 40 5 5 6-16 63 70 100 0 95 80 15 20 0 0 0 40 10 30 500 100 100 30 95 100 20 50 30 20 0 60 20 40 6-17 63 0 0 0 0 0 0 0 0 0 0 0 0 0 500 0 0 0 0 0 0 0 0 0 0 0 0 0 7-1  63 100 90 70 100 100 95 20 0 — 30 20 20 0 500 100 100 20 100 100 100 60 20 30 60 80 35 50 7-2  63 100 100 100 100 100 100 90 40 60 30 95 35 80 500 100 100 100 100 100 100 100 95 100 85 100 90 95 8-1  63 — — — — — — — — — — — — — 500 40 90 30 70 85 — 10 0 0 0 50 0 0 8-2  63 60 60 20 70 80 30 10 10 0 0 40 5 0 500 100 100 50 100 100 95 30 50 20 20 90 15 70 8-3  63 20 10 0 60 50 20 0 0 0 0 10 0 0 500 75 75 0 90 85 60 0 0 0 0 50 50 0 8-4  63 60 70 20 50 70 0 10 0 — 0 20 5 0 500 100 85 40 60 75 0 10 0 0 0 30 10 0 8-5  63 100 100 55 90 100 55 30 20 10 0 50 5 0 500 100 100 100 100 100 100 65 55 60 70 85 20 10 8-6  63 100 100 60 90 90 60 30 10 0 0 70 5 5 500 100 100 100 100 99 90 90 30 30 30 90 20 50 8-7  63 100 100 — 100 90 60 0 0 0 0 20 20 10 500 100 100 — 100 100 80 0 20 70 50 70 0 50 8-8  63 95 95 40 90 99 30 20 10 10 0 25 10 0 500 100 100 40 50 100 40 30 0 0 0 75 10 10 8-9  63 90 50 0 40 60 30 0 0 0 0 20 0 0 500 100 100 100 100 95 80 30 0 30 10 70 10 0 8-11 63 100 100 — 100 100 100 30 100 90 50 90 20 40 500 100 100 — 100 100 100 60 100 99 90 100 95 50 8-12 63 70 100 — 80 80 50 0 0 0 0 50 0 0 500 100 100 — 70 70 70 30 40 50 0 60 0 30 8-14 63 70 95 40 80 80 40 30 0 0 0 30 5 0 500 90 95 30 85 90 60 20 0 0 0 30 5 0 8-15 63 40 50 0 40 70 30 0 0 0 0 20 0 0 500 70 80 50 80 90 70 0 0 0 0 50 0 0 8-16 63 90 80 0 90 85 40 10 0 0 0 10 0 0 500 100 100 70 75 95 40 30 0 10 0 20 5 0 8-17 63 100 100 — 100 99 60 50 90 50 30 90 20 40 500 100 100 — 100 100 100 90 100 100 90 100 10 90 8-18 63 100 100 70 100 100 95 40 70 50 0 80 15 60 5400 100 100 100 100 100 60 70 70 90 10 70 20 40 8-19 63 100 100 70 100 100 90 60 50 50 30 65 30 40 500 100 100 90 100 100 90 90 50 50 30 80 30 60 8-20 63 100 100 90 100 95 90 70 20 90 30 90 15 15 500 100 100 100 100 100 100 95 40 100 30 100 20 60 8-21 63 100 100 — 90 99 60 0 0 10 0 90 10 50 500 100 100 — 100 100 90 40 70 70 60 100 0 60 8-22 63 95 100 50 80 100 80 20 70 0 0 65 5 5 500 100 100 80 100 100 100 75 30 30 30 95 15 10 8-23 63 95 100 70 50 95 50 0 0 0 0 25 0 0 500 99 100 100 100 99 100 20 0 20 0 60 5 0 8-24 63 100 95 — 70 50 0 0 10 0 50 0 10 20 500 100 100 — 80 80 50 20 0 50 20 40 10 30 8-25 63 100 100 70 100 90 90 70 20 40 10 70 10 10 500 100 100 100 100 100 90 95 65 60 40 90 25 60 8-26 63 — — — — — — — — — — — — — 500 0 0 0 0 0 0 0 0 0 0 0 0 0 8-27 63 90 80 30 50 90 60 50 0 30 10 70 5 0 500 100 100 100 80 100 85 50 10 20 20 80 10 5 8-28 63 100 100 50 90 90 50 30 10 40 20 50 10 10 500 100 100 100 95 100 90 90 80 60 30 90 20 40 8-29 63 100 100 100 100 100 90 90 80 90 50 90 40 60 500 100 100 100 100 100 100 100 100 100 100 100 70 100 8-30 63 90 100 100 100 95 90 60 10 20 0 95 15 5 500 100 100 100 100 100 99 95 40 95 10 100 40 80 8-31 63 70 70 0 80 90 50 10 0 0 0 70 5 0 500 100 100 80 80 95 95 40 20 30 50 70 10 5 8-32 63 90 100 10 100 95 50 10 0 0 0 30 5 0 500 100 100 100 100 100 90 40 10 20 0 80 5 10 8-33 63 95 100 55 90 90 60 20 20 10 0 55 5 0 500 100 100 95 100 100 100 80 40 30 50 70 15 10 8-34 63 50 95 30 100 95 50 20 10 0 0 50 5 0 500 100 100 100 100 100 95 65 0 50 40 90 15 40 8-35 63 95 100 — 40 80 10 40 0 40 0 20 10 20 500 100 100 — 95 99 10 60 80 80 10 90 10 50 8-36 63 100 100 — 100 95 20 0 50 30 30 30 10 40 250 100 100 — 95 99 20 30 40 90 60 90 10 30 8-37 63 90 100 100 95 90 30 0 0 0 0 90 0 0 500 95 100 95 80 90 60 30 10 50 0 100 40 35 8-38 63 60 100 30 40 40 20 0 0 0 0 10 0 20 250 70 100 30 40 50 50 20 0 0 0 20 20 50 8-39 63 70 100 100 100 50 60 10 0 0 0 60 15 15 250 80 100 30 90 70 80 10 30 10 10 80 10 15 8-40 63 80 100 30 40 60 80 0 0 0 0 80 0 0 250 90 100 75 100 80 20 10 0 0 0 60 10 0 8-41 63 40 95 30 30 40 90 0 0 0 0 30 0 0 250 40 100 100 100 50 30 0 0 0 0 60 0 0 8-42 63 50 100 0 60 50 40 0 0 0 0 20 0 0 250 95 100 0 70 80 90 0 0 0 0 60 0 0 8-43 63 60 100 95 100 90 100 40 20 20 0 80 20 10 250 90 100 100 100 100 100 60 30 30 20 100 30 30 9-1  63 100 100 30 100 95 20 30 70 20 90 10 20 500 100 100 30 100 100 90 100 99 50 100 70 80 9-2  63 100 100 30 100 100 10 10 10 0 40 5 15 500 100 100 95 80 95 60 80 70 30 80 60 30 9-3  63 100 100 20 100 95 20 0 10 30 80 10 20 500 100 100 95 100 100 95 90 90 95 100 80 90 9-4  63 95 100 90 100 80 30 70 70 10 95 40 80 500 100 100 100 90 100 95 100 98 95 100 80 70 9-5  63 100 90 40 100 90 30 20 50 0 50 10 50 500 100 100 100 90 100 90 100 100 80 95 70 80 9-6  63 100 100 40 100 100 20 90 100 90 80 40 30 500 100 100 100 100 100 100 100 100 100 100 75 70 9-7  63 100 100 90 100 100 40 60 80 10 80 30 20 500 100 100 90 100 100 70 70 90 30 90 80 80 9-8  63 100 100 30 95 95 30 10 30 10 50 15 30 500 100 100 30 100 100 75 95 90 30 75 80 80 9-9  63 100 100 90 90 90 20 10 40 10 95 30 70 500 100 100 100 100 100 90 100 100 90 100 95 98 9-10 63 100 100 40 100 100 20 20 60 10 100 25 50 500 80 100 50 100 100 70 95 95 20 80 90 70 9-11 63 100 100 30 100 80 20 0 20 40 95 15 20 500 100 100 80 100 100 40 50 80 80 100 40 50 9-14 63 100 100 60 95 80 80 10 40 30 90 20 15 500 100 100 100 100 100 100 100 100 100 95 98 90 9-15 125 100 100 100 100 100 95 90 95 90 100 70 90 500 100 100 100 100 100 100 99 100 100 100 90 95 9-16 63 100 100 100 100 100 100 100 100 100 100 100 100 500 100 100 100 100 100 100 100 100 100 100 100 100 9-17 63 95 100 0 100 80 10 0 0 10 100 10 15 500 95 100 0 95 90 10 60 80 10 100 60 70 9-21 63 100 100 100 100 100 90 70 60 30 99 25 60 500 100 100 100 100 100 100 100 90 90 100 60 80 9-22 63 100 100 30 100 90 10 20 0 10 80 5 0 500 100 100 70 100 100 80 90 80 50 80 30 40 9-23 63 85 45 10 50 70 0 0 0 0 10 0 0 500 95 90 30 75 95 10 50 30 0 50 15 20 9-24 63 100 100 30 100 100 70 30 30 40 70 20 10 500 100 100 80 100 100 95 90 70 75 90 30 50 9-25 63 100 95 50 100 100 30 10 10 0 60 15 5 500 100 100 100 100 100 80 90 70 60 80 35 35 9-26 63 100 100 100 100 100 100 80 90 80 100 40 40 500 100 100 100 100 100 100 100 100 80 100 70 60 9-28 63 90 90 10 95 80 25 0 0 0 40 5 5 500 100 100 50 100 100 50 10 30 0 80 40 15

The compositions of the present invention may be used in admixture with or in combination with other agricultural chemicals, fertilizers or phytotoxicity-reducing agents. In such a case, they may exhibit even better effects or activities. As other agricultural chemicals, herbicides, fungicides, antibiotics, plant hormones, insecticides, or acaricides may, for example, be mentioned. Especially with herbicidal compositions having the compounds of the present invention used in admixture with or in combination with one or more active ingredients of other herbicides, it is possible to improve the herbicidal activities, the range of application time(s) and the range of applicable weed types. Further, the compounds of the present invention and an active ingredient of another herbicide may be separately formulated so they may be mixed for use at the time of application, or both may be formulated together. The present invention covers such herbicidal compositions.

The blend ratio of the compounds of the present invention with the active ingredient of other herbicides can not generally be defined, since it varies depending on the time and method of application, weather conditions, soil type and type of formulation. However one active ingredient of other herbicide may be incorporated usually in an amount of 0.01 to 100 parts by weight, per one part by weight of the compounds of the present invention. Further, the total dose of all of the active ingredients is usually from 1 to 10000 g/ha, preferably from 5 to 500 g/ha. The present invention covers such herbicidal compositions.

As the active ingredients of other herbicides, the following (common name) may be mentioned. Herbicidal compositions having the compounds of the present invention used in combination with other herbicides, may occasionally exhibit a synergistic effect.

1. Those that are believed to exhibit herbicidal effects by disturbing auxin activities of plants, including a phenoxy acetic acid type such as 2,4-D, 2,4-DB, 2,4-DP, MCPA, MCPP, MCPB or naproanilide (including the free acids, esters or salts thereof), an aromatic carboxylic type such as 2,3,6 TBA, dicamba, dichlobenil, a pyridine type such as picloram (including free acids and salts thereof), triclopyr or clopyralid and others such as naptalam, benazolin or quinclorac.

2. Those that are believed to exhibit herbicidal effects by inhibiting photosynthesis of plants including a urea type such as diuron, linuron, isoproturon, chlorotoluron, metobenzuron, tebuthiuron or fluometuron, a triazine type such as simazine, atrazine, cyanazine, terbuthylazine, atraton, hexazinone, metribuzin, simetryn, ametryn, prometryn or dimethametryn, a uracil type such as bromacil, terbacil or lenacil, an anilide type such as propanil or cypromid, a carbamate type such as swep desmedipham or phenmedipham, a hydroxybenzonitrile type such as bromoxynil or ioxynil, and others such as pyridate, bentazon and methazole.

3. A quaternary ammonium salt type such as paraquat, diquat or difenzoquat, which is believed to be converted to free radicals by itself to form active oxygen in the plant and thus to exhibit quick herbicidal effects.

4. Those which are believed to exhibit herbicidal effects by inhibiting chlorophyll biosynthesis in plants and abnormally accumulating a photsensitizing peroxide substance in the plant body, including a diphenyl ether type such as nitrofen, lactofen, acifluorfen-sodium, oxyfluorfen, fomesafen, bifenox, or chlomethoxyfen, a cyclic amide type such as chlorphthalim, flumioxadine or flumiclorac-pentyl, and others such as oxadiazon, sulfentrazone or thidiazimin.

5. Those which are believed to exhibit herbicidal effects characterized by whitening activities by inhibiting chromogenesis of plants such as carotenoids including a pyridazinone type such as norflurazon, chioridazon or metflurazon, a pyrazol type such as pyrazolate, pyrazoxyfen or benzofenap, and others such as fluridone, fluramone, diflufencam, methoxyphenone, clomazone, amitrole, sulcotrione or isoxaflutole.

6. Those which exhibit herbicidal effects specifically to gramineous plants including an aryloxyphenoxypropionic acid type such as diclofop-methyl, pyrofenop-sodium, fluazifop-butyl, haloxyfop-methyl, quizalofop-ethyl, fenoxaprop ethyl, or cyhalofop-butyl and a cyclohexanedione type such as alloxydim-sodium, sethoxydim, clethodim or tralkoxydim.

7. Those which are believed to exhibit herbicidal effects by inhibiting amino acid biosynthesis of plants, including a sulfonylurea type such as chlorimuron-ethyl, nicosulfuron, metsulfuron-methyl, triasulfuron, primisulfuron, tribenuron-methyl, chlorosulfuron, bensulfuron-methyl, sulfometuron-methyl, prosulfuron, halosulfuron-methyl, thifensulfuron-methyl, rimsulfuron, azimsulfuron, flazasulfuron, imazosulfuron, cyclosulfamuron, flupyrsulfuron, a triazolopyrimidinesulfonamide type such as flumetsulam or metosulam, an imidazolinone type such as imazapyr, imazethapyr, imazaquin, imazamox, imazameth, imazamethabenz methyl, a pyrimidinesalicylic acid type such as pyrthiobac-sodium, bispyribac-sodium or pyriminobac-metbyl, and others such as glyphosate, glyphosate-ammonium, glyphosate-isopropylamine or sulfosate.

8. Those which are believed to exhibit herbicidal effects by interfering with the normal metabolism of inorganic nitrogen assimilation such as glufosinate, glufosinate-ammonium, phosphinothricin or bialophos.

9. Those which are believed to exhibit herbicidal effects by inhibiting cell division of plant cells, including a dinitroaniline type such as trifluralin, oryzalin, nitralin, pendamethalin, ethafluralin, benefin and prodiamine, an amide type such as bensulide, napronamide, and pronamide, a carbamate type such as propham, chlorpropham, barban, and asulam, an organophosphorous type such as amiprofos-methyl or butamifos and others such as DCPA and dithiopyr.

10. Those which are believed to exhibit herbicidal effects by inhibiting protein sysnthesis of plant cells, including a acetanilide type such as alachlor, metolachor, propachlor, acetochlor (including combinations with herbicide safeners) and dimethenamid.

11. Those in which the mode of action causing the herbicidal effects are not well understood including the dithiocarbamates such as thiobencarb, EPTC, diallate, triallate, molinate, pebulate, cycloate, butylate, vernolate or prosulfocarb and miscellaneous herbicides such as MSMA, DSMA, endothall, ethofumesate, sodium chlorate, pelargonic acid and fosamine.

Examples of combinations with Other Herbicides

(Note: Weed species abbreviations are from the Composite List of Weeds published by the Weed Science Society of America, 1989.)

The following examples illustrate the utility of combinations of compounds of this invention and existing herbicides. The methods used are identical to those for the application of single compounds except the commercial formulations of existing herbicides were added to the spray mixture in the appropriate amounts before spraying.

Combination Example 1. Pre-emergent application of Compound 9-1 with metolachlor

Percent Control of Broadleaf Weeds Treatment Rate (g ai/ha) AMARE ABUTH CASOB IPOHE CHEAL AMBEL Comp. 9-1  62.5 100 95 10 50 100 40 Metolachlor 1121 100 20 10 20  90 30 Comp. 9-1 +  62.5 + 100 100  100  70 100 80 Metolachlor 1121

Percent Control of Grass Weeds Treatment Rate (g ai/ha) SETVI ECHCG SORHA DIGSA Comp. 9-1 62.5 90 0 0 20 Metolachlor 1121 100 100 100 100 Comp. 9-1 + 62.5 + 100 100 100 100 Metolachlor 1121

Combination Example 2. Pre-emergent application of Compound 9-1 with dimethenamid

Percent Control of Broadleaf Weeds Treatment Rate (g ai/ha) AMARE ABUTH CASOB IPOHE CHEAL AMBEL Comp. 9-1  62.5 100 95 10 50 100 40 Dimethenamid 520 100 40 40  0  30 40 Comp. 9-1 +  62.5 + 100 100  70 100  100 100  Dimethenamid 520

Percent Control of Grass Weeds Treatment Rate (g ai/ha) SETVI ECHCG SORHA DIGSA Comp. 9-1 62.5 90 0 0 20 Dimethenamid 1121 100 100 100 100 Comp. 9-1 + 62.5 + 100 100 100 100 Dimethenamid 1121

Combination Example 3. Post-emergent application of Compound 9-1 with nicosulfuron

Percent Control of Broadleaf Weeds Treatment Rate (g ai/ha) AMARE ABUTH CASOB IPOHE CHEAL AMBEL Comp. 9-1 31.25 60 60  0 80 90 40 Nicosulfuron 23 70 55 30 70 70  0 Comp. 9-1 + 62.5 + 95 80 10 85 95 40 Nicosulfuron 23

Percent Control of Grass Weeds Treatment Rate (g ai/ha) SETVI ECHCG SORHA DIGSA Comp. 9-1 31.25 10 0 10 10 Nicosulfuron 23 85 95 85 80 Comp. 9-1 + 31.25 + 90 90 95 60 Nicosulfuron 23

Combination Example 4. Postemergent application of Compound 9-1 with pyridate

Percent Control of Broadleaf Weeds Treatment Rate (g ai/ha) AMARE ABUTH CASOB IPOHE CHEAL AMBEL Comp. 9-1  31.25 60 60  0 80 90 40 Pyridate 527 90 60 10 80 85 40 Comp. 9-1 +  31.25 + 95 100  40 100  90 85 Pyridate 527

Percent Control of Grass Weeds Treatment Rate (g ai/ha) SETVI ECHCG SORHA DIGSA Comp. 9-1 31.25 10 0 10 10 Pyridate 527 95 50 10 10 Comp. 9-1 + 31.25 + 85 60 30 60 Pyridate 527

Those compounds also may show utility as chemical desiccants to be used as harvest aids for crops such as cotton and potatoes. Preliminary studies are conducted in a greenhouse in which potato plant foliage was sprayed with solutions containing different compounds described in this invention. Greater than 90% necrosis of leaf tissue was observed within 1 week after application, when 100 g to 1000 g ai/ha were included in the treatment. Likewise, when cotton plants were treated, 100% necrosis of leaf tissue was observed within 48 hours after treatment. 

What is claimed is:
 1. A compound represented by the formula (1) or its salts:

wherein X is hydrogen, halogen, cyano, nitro, or (C₁₋₆)haloalkyl; Y is halogen, nitro or (C₁₋₆)haloalkyl; Z is oxygen or sulfur; Q is

A₁ and A₂ are independently oxygen or sulfur; R₉ and R₁₀ are hydrogen, (C₁₋₆)alkyl, acyl, or (C₁₋₆)alkylsulfonyl or R₉ and R₁₀ may form a ring consisting of polymethylene, (CH₂)m groups, where m is an integer of 2, 3, 4, or 5, together with the nitrogen atom of NR₉R₁₀, which may or may not have a (C₁₋₆)alkyl substituent; and Ar is a substituted or unsubstituted aryl or heteroaryl ring.
 2. The compound or its salt according to claim 1, wherein X is hydrogen or halogen, and Y is halogen, and Z is oxygen or sulfur, and Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazolyl, or phenyl, or pyridyl, pyrimidyl, triazolyl, thiazolyl, isothiazolyl , or phenyl substituted with up to five substituents independently selected from halogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo(C₁₋₆)alkoxy, (C₁₋₆)alkylsulfonyl, (C₁₋₆)alkylsulfinyl, di(C₁₋₆)alkylaminocarbonyl, cyano, nitro, amino, hydroxy, (C₁₋₆)alkylsulfonylamino, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkoxy, (C₁₋₆)alkxylcarbonylamino, bisbenzoylamino, aminoacetyl, aminotrifluoroacetyl, or amino(C₁₋₆)alkylsulfonate.
 3. The compound or its salt according to claim 1, wherein X is fluorine, and Y is chlorine, and Ar is 2-pyridyl, 3-pyridyl , 4-pyridyl , 3-bromo-2-pyridyl, 5-bromo-2-pyridyl, 6-bromo-2-pyridyl, 3-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3-cyano-2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 3-nitro-2-pyridyl, 5-nitro-2-pyridyl, 6-nitro-2-pyridyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 5-amino-2-pyridyl, 3-dimethylaminocarbonyl-2-pyridyl, 3-methylsulfonyl-2-pyridyl, 3-isopropylsulfonyl-2-pyridyl, 6-chloro-3-trifluoromethyl-2-pyridyl, 3,5,6-trifluoropyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-bromo-2-pyrimidyl, 4-chloro-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl, 4,6-dimethoxy-2-pyrimidyl, 2,6-dimethoxy-4-pyrimidyl, 4,6-dimethoxy-2-triazinyl, phenyl, 2-iodophenyl, 2-trifluoromethoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-methylsulfonylaminophenyl, 4-(1-ethoxycarbonylethoxy)phenyl, 2-cyanophenyl, 2-cyano-3-fluorophenyl, 2-cyano-4-fluorophenyl, 2-amino-4-(1-ethoxycarbonylethoxy)-phenyl, 2-cyano-4-nitrophenyl, 4-amino-2-cyanophenyl, 4-nitro-2-trifluoromethylphenyl, 4-amino-2-trifluoromethylphenyl, 4-acetylamino-2-trifluoromethylphenyl 4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 5-chloro-4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 3-methyl-4-nitro-5-isothiazolyl, or 5-nitro-2-thiazolyl.
 4. The compound or its salt according to claim 1 wherein Ar is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, phenyl, 2-nitrophenyl, 4-nitrophenyl, or 2-cyanophenyl.
 5. The compound or its salt according to claim 1 wherein Ar is 2-pyridyl, 3-pyridyl, 4-pyridyl , 3-bromo-2-pyridyl, 5-bromo-2-pyridyl, 6-bromo-2-pyridyl, 3-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3-cyano-2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 3-nitro-2-pyridyl, 5-nitro-2-pyridyl, 6-nitro-2-pyridyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 5-amino-2-pyridyl, 3-dimethylaminocarbonyl-2-pyridyl, 3-methylsulfonyl-2-pyridyl, 3-isopropylsulfonyl-2-pyridyl, 6-chloro-3-trifluoromethyl-2-pyridyl, 3,5,6-trifluoropyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-bromo-2-pyrimidyl, 4-chloro-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl, 4,6-dimethoxy-2-pyrimidyl, 2,6-dimethoxy-4-pyrimidyl, 4,6-dimethoxy-2-triazinyl, phenyl, 2-iodophenyl, 2-trifluoromethoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-methylsulfonylaminophenyl, 4-(1-ethoxycarbonylethoxy)phenyl, 2-cyanophenyl, 2-cyano-3-fluorophenyl, 2-cyano-4-fluorophenyl, 2-amino-4-(1-ethoxycarbonylethoxy)-phenyl, 2-cyano-4-nitrophenyl, 4-amino-2-cyanophenyl, 4-nitro-2-trifluoromethylphenyl, 4-amino-2-trifluoromethylphenyl, 4-acetylamino-2-trifluoromethylphenyl, 4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 5-chloro-4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 3-methyl-4-nitro-5-isothiazolyl, or 5-nitro-2-thiazolyl.
 6. A process for producing a compound represented by the formula (I) in claim 1 or its salt, said process comprising reacting a compound represented by the formula:

with a compound of the formula: Ar-Hal wherein Hal is a halogen atom, in the presence of a base.
 7. A process for producing a compound or its salt represented by the formula (I) in claim 1 and having the formula (XXXIII)

wherein said process comprising reacting the isocyanate of formula (III):

with the hydrazono-ester (XLIII) of the formula:

wherein alkyl is an alkyl group.
 8. A process for producing a compound or its salt represented by the formula (I) in claim 1 and having the formula (XXXIII):

said process comprising reacting a compound represented by formula (III):

with alkyl 3-amino-4,4,4-trifluorocrotonate in the presence of a base and quenching the reaction with an animating agent.
 9. A process for producing a compound or its salt represented by the formula (XXXV)

said process comprising reacting a haloaryl uracil of formula (XXXVIII):

with the salt of an Ar—Z—H; wherein X is hydrogen, halogen, cyano, nitro, or C₁₋₆ haloalkyl; Y is halogen, nitro or C₁₋₆ haloalky; Ar is a substituted or unsubstituted aryl or heteroaryl ring; Hal is a halogen atom and Z is oxygen or sulfur.
 10. A herbicidal composition, characterized in that it contains at least one compound or its salt according to claim
 1. 11. A herbicidal composition which comprises an effective amount of a compound or its salt of claim 1 and an agricultural adjuvant.
 12. A method for controlling weeds, which comprises applying to the locus to be protected a herbicidally effective amount of a compound or its salt of claim
 1. 13. A method for controlling weeds in a corn field which comprises applying a herbicidally effective amount of a compound or its salt of claim 1 to the corn field.
 14. A method for controlling weeds in a soybean field which comprises applying a herbicidally effective amount of a compound or its salt of claim 1 to the soybean field.
 15. A method for controlling weeds, which comprises applying to the locus to be protected a herbicidally effective amount of a compound or its salt of claim 1 in combination with another herbicide for providing an additive or synergistic herbicidal effect.
 16. A method for controlling weeds of claim 15 wherein the another herbicide is an acetanilide or sulfonylurea.
 17. A method to desiccate a plant which comprises applying to the plant a compound or its salt of claim
 1. 18. A method to desiccate a plant of claim 17 wherein the plant to which the compound or its salt is applied is a potato plant or a cotton plant.
 19. A method for controlling weeds as in claim 12 wherein the compound or its salt is applied to the soil as a preemergent herbicide.
 20. A method for controlling weeds as in claim 12 wherein the compound or its salt is applied to plant foliage. 